Introduction to CNS Pharmacology (PDF)

Introduction to Central Nervous System Pharmacology Dr. Leila Alblowi Lecture Objectives : Identify and classify neurotransmitters involved in CNS pharmacology. Understand the mechanisms of action for GABA and its role in neuronal signaling. Discuss pharmacologic agents that modulate GABAe...

Introduction to Central Nervous System Pharmacology Dr. Leila Alblowi Lecture Objectives : Identify and classify neurotransmitters involved in CNS pharmacology. Understand the mechanisms of action for GABA and its role in neuronal signaling. Discuss pharmacologic agents that modulate GABAergic neurotransmission. Understand the mechanisms of action for glutamate and its role in neuronal signaling Analyze the clinical implications of GABA and glutamate modulation in treatment.  Neurotransmitters Central Nervous System (CNS): Uses a wide variety of small molecule neurotransmitters and neuroactive peptides. ▪ Neurotransmitter categories based on both their structure and function Amino acid neurotransmitters: Biogenic amine neurotransmitters 1. Glutamate 1. Dopamine 2. Aspartate 2. Norepinephrine 3. GABA 3. Epinephrine 4. Glycine 4. Serotonin 5. Histamine Others: 1. Acetylcholine 2. Adenosine 3. Nitric oxide (NO) ( lipid-soluble gas) Amino Acid Neurotransmitters ▪ Excitatory neurotransmitters in the CNS Glutamate Aspartate ▪ Inhibitory neurotransmitters in the CNS GABA Glycine GABAERGIC NEUROTRANSMISSION PHYSIOLOGY OF GABAERGIC NEUROTRANSMISSION ▪ GABA functions as the primary inhibitory in the CNS. ▪ It decreases neuronal excitability through several mechanisms. ▪ Drugs that modulate GABA receptors affect: ✓Attention Modulation of GABA signalling is ✓Memory also an important mechanism for the treatment of neuronal ✓Anxiety hyperactivity in epilepsy. ✓Sleep ✓Muscle tone GABA Synthesis and release ▪ GABA is formed from glutamate by the action of glutamic acid decarboxylase (GAD). GAD ▪ Glutamate GABA ▪ GAD requires pyridoxal phosphate (vitamin B6) as a cofactor ▪ GABA is packaged into presynaptic vesicles by a vesicular transporter (VGAT). ▪ In response to an action potential and an increase in intracellular Ca2+ levels in the presynaptic neuron, GABA is released into the synaptic cleft through the fusion of vesicles containing GABA with the presynaptic membrane. GABA uptake and Metabolism ▪ Uptake: GABA reuptake after release via specific transporters (GAT) by GABAergic neurons and other neurons. GABA transport is inhibited by tiagabine (used to treat epilepsy). ▪ Metabolism: ▪ GABA transaminase (GABA-T) converts GABA into succinic semialdehyde (SSA). ▪ SSA is oxidized to succinic acid ▪ Succinic acid is further processed to form α-ketoglutarate. ▪ GABA-T regenerates glutamate from α-ketoglutarate. GABA inhibitory neurotransmitter ▪ Inhibitory neurotransmitters cause the inside of the cell to become more negative, making it harder for the cell to activate. This happens by opening K+ or Cl− channels: K+ flows out, or Cl− flows in. This leads to a loss of positive charge or a gain of negative charge inside the cell. As a result: The membrane becomes more negative (hyperpolarized). The membrane’s resistance decreases. It becomes harder for positive currents to make the membrane activate (depolarize) GABA Receptors 1. Ionotropic GABA receptors: ▪ GABAA ▪ GABAC ▪ ligand-gated ion channels (open an intrinsic chloride ion channel) 2. Metabotropic GABA receptors ▪ GABAB ▪ G protein coupled receptors ▪ Activate neuronal potassium channels through second messengers GABAA receptors ▪ Structure of GABA-A Receptors: ▪ Composed of 5 subunits: two α, two β, and one γ. ▪ Binding Sites: ▪ GABA binds at the active site located between α and β subunits. ▪ Additional allosteric binding sites exist for other agonists. ▪ Location and Function: ▪ Primarily located on postsynaptic membranes. ▪ Mediate postsynaptic inhibition. GABAA receptors ▪ Mechanism of Action: GABA-A channels are selectively permeable to Cl− ions. Upon activation by GABA, Cl− influx increases. This influx leads to membrane hyperpolarization. Resulting in an inhibitory effect that reduces the likelihood of action potentials in the CNS. GABAB receptors ▪ Mechanism of Action: ▪ G protein-coupled receptors that couple through Gi to inhibit voltage-gated Ca2+ channels ▪ Leading to reduce in transmitter release, to open potassium channels (thus reducing postsynaptic excitability) and to inhibit adenylyl cyclase. ▪ Reduction in cAMP (Minor effects on cellular excitability) ▪ Location : ▪ Presynaptic: Reducing Ca2+ influx ▪ Postsynaptic: Activation of K+ channels Pharmacologic classes and agents affecting GABAergic neurotransmission ▪ Pharmacologic agents acting on GABAergic Therapeutic agents that activate neurotransmission affect GABA: GABAA receptors are used for: 1. Sedation Metabolism 2. Anxiolysis Transport 3. Hypnosis (general anaesthesia) Receptor activity 4. Neuroprotection following a stroke or head trauma ▪ Most pharmacologic agents affecting GABAergic 5. Control of epilepsy neurotransmission act on the ionotropic GABAA receptor. Inhibitors of GABA Metabolism and Transport Tiagabine ▪ Is a competitive inhibitor of the GABA transporters (GAT-1) ▪ Major clinical indication: ▪ Epilepsy ▪ By inhibiting GABA reuptake, tiagabine increases both synaptic and extra-synaptic GABA concentrations. ▪ Adverse effects: ▪ Confusion ▪ Sedation ▪ Amnesia ▪ Ataxia Inhibitors of GABA Metabolism and Transport Vigabatrin: ▪ Is inhibitor of GABA transaminase (GABA-T) ▪ Blocks the conversion of GABA to succinic semialdehyde, resulting in: High intracellular GABA concentrations Increased synaptic GABA release ▪ Used in: ▪ Epilepsy ▪ Investigated for treatment of: ▪ Drug addiction ▪ Panic disorder ▪ Obsessive-compulsive disorder (OCD) GABAA Receptor Modulators Benzodiazepines (BZDs) MOA: ▪ Benzodiazepines (BZDs) bind to a specific allosteric site on the GABA-A receptor located at the α/γ subunit interface. ▪ This binding increases the receptor's affinity for GABA. ▪ The increased affinity enhances the frequency of chloride channel opening ▪ More Cl⁻ ions enter the neuron. ▪ The influx of Cl⁻ causes hyperpolarization of the neuronal membrane. ▪ This hyperpolarization inhibits the formation of action potentials, enhancing the inhibitory effect of GABA GABAA Receptor Modulators Benzodiazepines (BZDs) Clinical Applications: ▪ Sleep enhancers ▪ Anxiolytics ▪ Sedatives ▪ Antiepileptics ▪ Muscle relaxants ▪ To treat Ethanol withdrawal symptoms  GABAA Receptor Modulators Benzodiazepines (BZDs) ▪ Half-lives of BZDs and duration of action also determine therapeutic usefulness. ▪ Midazolam : ultrashort-acting ( hypnotic and IV anesthetic ▪ Lorazepam : short-acting (12-18h) > hypnotic and anxiolytic ▪ Alprazolam : intermediate-acting (24h) > anxiolytic ▪ Diazepam : long-acting (24-48h) > anxiolytic, muscle relaxant and anticonvulsant  GABAA Receptor Modulators Benzodiazepines (BZDs) ▪ Adverse effects: High doses of benzodiazepines rarely cause death unless administered with other drugs, such as: ▪ most common drowsiness and Ethanol confusion, may also cause impaired CNS depressants motor skills (ataxia), cognitive Opioid analgesics impairments The enhanced CNS depression seen with related ethanol use is due to: Synergistic effects on GABAA receptors Ethanol-mediated inhibition of CYP3A4 (↓clearance of BZD)  GABAA Receptor Modulators Benzodiazepines (BZDs) ▪ Tolerance and Dependence: ▪ Chronic benzodiazepine use induces tolerance ▪ Manifested as a decrease in the efficacy of both benzodiazepines and barbiturates ▪ Tolerance to benzodiazepines results from: Decreased expression of benzodiazepine (GABAA ) receptors at synapses.(down- regulation of receptor ) Uncoupling of the benzodiazepine binding site from the GABA site.  GABAA Receptor Modulators Benzodiazepines (BZDs) ▪ Sudden cessation after chronic benzodiazepine administration can result in a withdrawal syndrome characterized by: Benzodiazepines Overdose: ▪ Confusion Can be reversed by a benzodiazepine ▪ Anxiety antagonist such as Flumazenil A competitive BDZ receptor antagonist ▪ Agitation ▪ Insomnia  GABAA Receptor Modulators Barbiturates Mechanism of action: ▪ Potentiate the inhibitory GABA activity by increasing the duration of Cl- channel openings at specific binding site of GABA A receptor. ▪ Also inhibit excitatory glutamate (AMPA) receptors. Actions: ▪ Depression of CNS: dose-dependent (sedation >> hypnotic >> anesthetic >> coma and death). ▪ Respiratory depression: overdose resulting in respiratory depression & death.  GABAA Receptor Modulators Barbiturates Examples of barbiturates and therapeutic uses: Overdose may produce: ▪ Phenobarbital, anticonvulsant ▪ Profound hypnosis ▪ Thiopental, general anesthetic ▪ Coma ▪ Pentobarbital, hypnotic(Decreases the activity of voltage ▪ Respiratory depression dependent Na+ channels → Inhibiting high-frequency ▪ Death neuronal firing) ▪ They have been largely replaced by BZDs.  GABAA Receptor Modulators Barbiturates Adverse Effects: Benzodiazepines have largely replaced barbiturates in most clinical ▪ Unlike benzodiazepines, high doses of barbiturates can cause: applications because benzodiazepines are: ▪ Fatal CNS and respiratory depression Safer ▪ The concomitant administration of barbiturates Cause less tolerance and other CNS depressants, often ethanol,: → Have fewer withdrawal symptoms Results in sever CNS depression Induce less profound effects on drug- metabolizing enzymes (barbiturates are enzyme inducers) GABAA Receptor Modulators Barbiturates Tolerance and Dependence: Development of physiologic dependence results in a drug withdrawal syndrome ▪ Repeated and extended misuse characterized by: (induces tolerance and physiologic dependence). ▪ Tremor ▪ Prolonged barbiturate use: ▪ Anxiety ✓Increases the activity of cytochrome ▪ Insomnia P450 enzymes ▪ CNS excitability ✓Accelerates barbiturate metabolism ▪ If left untreated may progress to: Seizures & Cardiac arrest Other drugs that act on GABAA receptors ▪ Vast majority of anaesthics potentiate the action of GABA at GABAA receptors. ▪ Examples: propofol & etomidate GABAB Receptor Agonists Baclofen ▪ Is a selective GABAB receptor agonist. ▪ Is the only compound currently in clinical use that targets GABAB receptors ▪ Used to treat spasticity associated with motor neuron disorders (e.g. multiple sclerosis). Glutamate neurotramsmission Glutamate ▪ The main excitaory neurotransmitter in the CNS. ▪ Glutamate and aspartate : excitatory amino acids (EAAs) - the main fast excitatory transmitters in the CNS.  Glutamate ▪ Excitatory amino acid neurotransmitters induce depolarizing the membrane. 1. Open sodium channel (cation-specific channels): ✓Cause a net influx of sodium ions ✓Depolarizes the membrane or 2. Closes potassium “leak channels” ✓Reduce the outward flow of potassium ions ✓Depolarize the membrane  Glutamate Metabolism Glutamate synthesis occurs via two distinct pathways: 1. Pathway: CNS nerve terminal: α-ketoglutarate formed in the Krebs cycle is transaminated to glutamate , a step that is directly linked to GABA conversion 2. Pathway: Glial cells: Glutamine produced and secreted by glial cells is transported into nerve terminals and converted to glutamate by glutaminase Glutamine glutaminase Glutamate Glutamate Metabolism Released: In glial cells: Glutamate is stored in synaptic The enzyme glutamine synthetase converts vesicles glutamate to glutamine released via calcium-dependent exocytosis Glutamine generated in glial cells: 1. Recycled into nerve terminals and converted back to glutamate. Reuptake: Glutamate is removed from the synaptic 2. Enters the Krebs cycle, forming α- cleft by glutamate reuptake transporters ketoglutarate to replenish levels used in located on: glutamate synthesis. ✓Presynaptic nerve terminals ✓Plasma membrane of glial cells Glutamate Receptors Glutamate receptors are divided into: 1. Ionotropic receptors 2. Metabotropic receptor Ionotropic Glutamate Receptors There are three main subtypes , ▪ Ionotropic glutamate receptors mediate classified according to their activation fast excitatory synaptic responses by the selective agonists: 1. AMPA ▪ Activation of the receptor → Permit the 2. Kainate flow across plasma membranes of: 3. NMDA ✓Na+ ions ✓K+ ions ✓Ca2+ ions Ionotropic Glutamate Receptors Ionotropic Glutamate Receptors AMPA receptors ▪ Located throughout the CNS ▪ Four AMPA receptor subunits (GluR1–GluR4) ▪ AMPA receptor (+):Na+ influx , K+ efflux Kainate receptors ▪ Expressed throughout the CNS ▪ Five kainate receptor subunits have been identified ▪ Like AMPA receptors, kainate receptors allow: Na+ influx ,K+ efflux Ionotropic Glutamate Receptors NMDA (N-methyl-D-aspartate) receptors ▪ Expressed primarily in the hippocampus, cerebral cortex, and spinal cord. ▪ Glutamate and Glycine bind to NMDA receptor and cause activation: → Opens a channel that allows: ✓K+ efflux ✓Na+ efflux ✓Ca2+ influx  Metabotropic Glutamate Receptors Group I receptors (postsynaptic): ▪ Eight different metabotropic glutamate ✓Cause excitation by activating a nonselective receptors (mGlu1–8) are divided into three cation channel groups (I, II, and III) ✓Also activate phospholipase C, leading to IP3- ▪ G protein coupled receptors mediated intracellular Ca2+ release Group II and group III receptors (Presynaptic): ▪ Regulate cell excitability and synaptic ✓Act as inhibitory auto-receptors transmission ✓Cause inhibition of adenylyl cyclase and decreased cAMP generation Glutamate transporters ▪ Maintaining extracellular glutamate levels within a physiological range is crucial to prevent overexcitation and neurotoxicity. ▪ Glutamate transporters, known as excitatory amino acid transporters (EAAT), play a key role in this regulation. ▪ Key membrane glutamate transporters include: ✓ EAAT1 (GLAST) ✓ EAAT2 (GLT1) ✓ EAAT3 (EAAC1) ▪ These transporters are essential for regulating glutamate uptake across various regions of the CNS.  Glutamate transporters ▪ Multiple studies have demonstrated that decreased expression and function of glutamate transporters contribute to the development of various neurological disorders, such as: 1.Cerebral ischemia 2.Epilepsy 3.Spinal cord injury 4.Amyotrophic lateral sclerosis (ALS) 5.AIDS neuropathy 6.Alzheimer’s disease Amyotrophic lateral sclerosis (ALS) ▪ Patients with ALS have impaired glutamate transporters in the spinal cord and motor cortex. ▪ These abnormal glutamate transporters permit the accumulation of high glutamate Riluzole: Voltage-gated sodium channel blocker concentrations in the synaptic cleft, Acts by reducing Na+ conductance and so possibly leading to motor neuron death via decreasing glutamate release. The drug may also directly antagonize NMDA excitotoxicity. receptors. → Prolongs survival and decreases disease progression in ALS Alzheimer’s disease ▪ Neurotransmitter pathological features: Memantine: Noncompetitive NMDA receptor ▪ Deficiency in acetylcholine leading to antagonist. memory loss (hallmark of AD) Used in the treatment of Alzehimer disease. ▪ Overstimulation of glutamate ▪ Pharmacotherapy for Alzheimer’s disease: ▪ Acetylcholinesterase inhibitors ▪ NMDA-receptor channel blocker (memantine) Epilepsy ▪ Seizures can occur due to: ▪ Main mechanisms of action of antiseizure medications: Overstimulation of glutamatergic pathways: ▪ Block voltage-gated sodium channels Initiated by excessive activation ▪ Block voltage-gated calcium channels of AMPA receptors ▪ Potentiate GABA inhibitory effect Followed by overactivation of NMDA receptors ▪ Inhibit glutamate excitatory mechanism Epilepsy ▪ Lamotrigine: ▪ Felbamate ▪ A drug used in the treatment of ▪ Is antiepileptic agent seizures ▪ Has a variety of actions, including: ▪ Stabilizes the inactivated state of the ▪ The inhibition of NMDA receptors voltage-gated Na+ channel and thereby reduces: ▪ Because of associated: ▪ Membrane excitability ↓ 1. Aplastic anemia ▪ Glutamate release ↓ 2. Hepatotoxicity ▪ Glutamate receptor activation↓ ▪ ✓Its use is restricted to patients with refractory seizures