Pharmacology of the Central Nervous System PDF

Pharmacology Iva D. Tzvetanova, Ph.D. Office Hours: Currently by appointment Email: [email protected] Link to Office Hours Booking: https://outlook.office365.com/owa/calendar/[email protected]/bookings/ Your Attendance is MANDATORY How did you do in the MD310 Midterm Exam...

Pharmacology Iva D. Tzvetanova, Ph.D. Office Hours: Currently by appointment Email: [email protected] Link to Office Hours Booking: https://outlook.office365.com/owa/calendar/[email protected]/bookings/ Your Attendance is MANDATORY How did you do in the MD310 Midterm Exam? F2023 – Midterm Exam Results PD Treatment Summary Simmons Pharmacology: An Illustrated Review; Katzung’s Basic & Clinical Pharmacology Levodopa Levodopa i.e. l-3,4-dihydroxyphenylalanine (l-dopa) Drug interactions  Pyridoxine  Form of vitamin B6 found in multivitamins  Cofactor for dopa decarboxylase ➔ May enhance the metabolism of l-DOPA Antipsychotics  Antagonists of dopamine receptors ➔Contraindicated with l-DOPA  Reserpine  Depletes dopamine ➔ Contraindicated  Monoamine oxidase inhibitors (MAOIs)  Block dopamine breakdown ➔ May exaggerate effects (hypertensive crisis and hyperpyrexia) ➔ MAOIs should be withdrawn at least 2 weeks prior to l-DOPA administration  Anticholinergics - may slow gastric emptying Lippincott Illustrated Reviews: Pharmacology, 7th Edition Levodopa Levodopa i.e. l-3,4-dihydroxyphenylalanine (l-dopa) Contraindications Care must be exercised in patients with:  Heart disease  Cerebrovascular disease  Neurological disease Combination Therapy Aimed at Increasing Dopamine Synthesis L-DOPA ➔  dopamine synthesis BUT l-DOPA can be degraded in the periphery by AAAD ➔ co-administer Carbidopa BBB - Carbidopa – does NOT cross BUT inhibits AAAD ➔ more l-DOPA can reach the brain BUT Katzung’s Basic & Clinical Pharmacology, 13th edition Combination Therapy Aimed at Increasing Dopamine Synthesis L-DOPA ➔  dopamine synthesis BUT l-DOPA can be degraded in the periphery by AAAD ➔ co-administer Carbidopa BBB - Carbidopa – does NOT cross BUT inhibits AAAD ➔ more l-DOPA can reach the brain BUT l-DOPA can be degraded by COMT in the periphery Brody’s Human Pharmacology Summary of Drugs Used for the Treatment of Parkinson’s Disease Katzung’s Basic & Clinical Pharmacology, 13th edition Summary of Drugs Used for the Treatment of Parkinson’s Disease Katzung’s Basic & Clinical Pharmacology, 13th edition We have so many drugs to treat Parkinson’s BUT Why is there still a problem? Disease Still Progresses We have so many drugs to treat Parkinson’s BUT Why is there still a problem? On- off phenomenon with dopamine supplementation therapy • Levodopa & dopamine agonists – improve & control motor symptoms for several years BUT • After an initial «honeymoon period» - i.e. when it works well – patients develop multiple problems: • such as lack of response, fluctuating response or dyskinesia • "off” period = decreased mobility • "on” period = medication is working & symptoms are controlled • 40 % of patients will experience motor fluctuations within 46 years of onset, –  by 10 % per year after that. On- off phenomenon with dopamine supplementation therapy • Goal –  "off" time as much as possible – Make “off” time as predictable as possible – treat it with as little medication as possible (so as to avoid side effects such as psychosis & dyskinesia) On- off phenomenon with dopamine supplementation therapy • Dopamine supplementation therapy – does not address all symptoms • Also Side effects – Sensory symptoms (e.g. pain, fatigue, and motor restlessness) – Autonomic symptoms (e.g. urinary incontinence & profuse sweats) – Psychiatric disorders (e.g. depression, anxiety & psychosis • It may even aggravate the neuropsychiatric disturbances • Neurodegeneration persists Other Movement Disorders • Huntington’s disease: an inherited adult-onset neurodegenerative disorder characterized by dementia & bizarre involuntary movements. Neuronal loss in projection neurons in the dorsal striatum. • Tourette’s syndrome: a neurologic disease of unknown cause that presents with multiple tics associated with snorting, sniffing, and involuntary vocalizations (often obscene) • Wilson’s disease: an inherited (autosomal recessive) disorder of copper accumulation in liver, brain, kidneys, and eyes; symptoms include jaundice, vomiting, tremors, muscle weakness, stiff movements, liver failure, and dementia Katzung’s Basic & Clinical Pharmacology, 13th edition Parkinson’s Disease – the Essentials See You Tomorrow Connolly & Lang JAMA 2014 Pharmacology of the Central Nervous System Glutamatergic and GABAergic Neurotransmission + Sedative & Hypnotic Drugs GABAergic and Glutamatergic Neurotransmission GABA = γ-aminobutyric acid GABA = 1° inhibitory neurotransmitter in the CNS Glutamate = 1° excitatory neurotransmitter in the CNS Simplified View of the Effects of Excitatory and Inhibitory Neurotransmitters Excitatory - Glutamate Note: Both neurotransmitters bind to metabotropic receptors as well Influx +vely charged ions Influx –vely charged ions Reduced efflux of +vely charged ions Efflux +vely charged ions Depolarize the membrane K+ channel closed ➔ Membrane resistance ➔responsiveness to excitatory current Inhibitory - GABA Hyperpolarize the membrane Membrane resistance – shunting ➔responsiveness to excitatory current STUDY HELP CNS – Neurotransmitter Receptors and Effectors Simmons Pharmacology: An Illustrated Review A Single Neuron Receives Multiple Inputs Katzung’s Basic & Clinical Pharmacology, 13th edition A Single Neuron Receives Multiple Inputs Long-tract neurons can participate in convergent and divergent signaling Local circuits consist of excitatory and inhibitory neurons layered in complicated structural motifs Single-source divergent neurons relay information to a multitude of brain areas and hundreds of neurons Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy A Single Neuron Receives Multiple Inputs E = excitatory e.g. glutamate I = inhibitory e.g. GABA Katzung’s Basic & Clinical Pharmacology, 13th edition Let’s Start with γ-aminobutyric acid (GABA) Why is GABAergic Neurotransmission an Important Pharmacological Target? • Pharmacological modulation of GABAegic neurotransmission affects: • Arousal and attention • Memory formation • Anxiety • Sleep • Muscle tone • Treatment of focal or widespread neuronal hyperactivity observed in • Epilepsy Let’s Start with γ-aminobutyric acid (GABA) Well we cannot REALLY Neuronal Communication – the Basics Presynaptic action potential arrives Ca2+ influx into the presynaptic terminal Neurotransmitter is released into the synaptic cleft Neurotransmitter binds to receptor on the postsynaptic cell Transduction of the message + integration of signals from multiple inputs Response Reconstruction of docked vesicles Courtesy of Ben Cooper (MPIEM) Neurotransmitter is degraded/recycled ➔ Response can be terminated How is GABA Synthesized? From Glutamate GABA and Glutamate Synthesis and Metabolism are Intertwined Neuronal Communication – the Basics Presynaptic action potential arrives Ca2+ influx into the presynaptic terminal Neurotransmitter is released into the synaptic cleft Neurotransmitter binds to receptor on the postsynaptic cell Transduction of the message + integration of signals from multiple inputs Response Reconstruction of docked vesicles Courtesy of Ben Cooper (MPIEM) Neurotransmitter is degraded/recycled ➔ Response can be terminated Neurons Actually Rarely Work Alone Katzung’s Basic & Clinical Pharmacology, 13th edition Glutamate Degradation Involves Astrocytes Katzung’s Basic & Clinical Pharmacology, 13th edition Glutamate Degradation Involves Astrocytes – a Word About the Tripartite Synapse Glutamate in the cleft Glial glutamate transporters take up glutamate Glial glutamine synthetase breaks glutamate to glutamine Glutamine is transferred to the presynaptic neuron Glutamate can also be taken up into the presynaptic neuron directly Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Astrocytes Supply Glutamine to GABAergic and Glutamatergic Neurons Figure is on the next slide Simmons Pharmacology: An Illustrated Review GABA Synthesis and Metabolism GABA-T = GABA transaminase Converts α-ketogluterate to glutamate GAD = Glutamic Acid Decarboxylase Converts glutamate to GABA in GABAergic neurons Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy GABA Synthesis and Metabolism GABA-T = GABA transaminase (mitochondrial) Also degrades GABA Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy GABA Synthesis and Metabolism Simmons Pharmacology: An Illustrated Review Simmons Pharmacology: An Illustrated Review How Do We Terminate the Action of GABA? By removing of GABA from the synaptic cleft via uptake transporters in astrocytes and presynaptic neurons What are the transporters called? GABA transporters (GATs) Pharmacological Agents Regulating GABA Metabolism and Transport These drugs are mostly used for experimental purposes, but not only Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Neuronal Communication – the Basics Presynaptic action potential arrives Ca2+ influx into the presynaptic terminal Neurotransmitter is released into the synaptic cleft Neurotransmitter binds to receptor on the postsynaptic cell Transduction of the message + integration of signals from multiple inputs Response Reconstruction of docked vesicles Courtesy of Ben Cooper (MPIEM) Neurotransmitter is degraded/recycled ➔ Response can be terminated GABA Receptors Clinically useful drugs target these STUDY HELP CNS – Neurotransmitter Receptors and Effectors Simmons Pharmacology: An Illustrated Review STUDY HELP CNS – Neurotransmitter Receptors and Effectors Simmons Pharmacology: An Illustrated Review The other GABAergic Receptor The GABAB receptor is a G-protein coupled receptor Activation leads to inhibition of adenylyl cyclase ➔ cAMP Opening of K+ channels – βγ subunits Closing of Ca2+ channels – βγ subunits Clinically usefull drug – baclofen Agonist ➔ muscle relaxant Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy GABAA and GABAC Receptors: The Ionotropic GABA Receptors The Ionotropic GABA Receptors GABAA receptor = chloride ion channel  Complex consists of five or more membranespanning subunits  Multiple forms of α, β, and γ subunits are arranged in different pentameric combinations ➔ GABAA receptors exhibit molecular heterogeneity  GABA interacts at two sites between the α and β subunits Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy; Katzung’s Basic & Clinical Pharmacology The Ionotropic GABA Receptors GABA secreted in the cleft GABA binds ionotropic receptor Channel opens Cl- enters the postsynaptic neuron Postsynaptic membrane is hyperpolarized  Responsiveness to excitatory current Simmons Pharmacology: An Illustrated Review Binding Sites of Some GABAA Receptor Summary of GABA Pharmacotherapeutics A Modulators Brody’s Human Pharmacology Summary of GABAA Pharmacotherapeutics BUT increased of GABA receptor activity can lead to:  Sedation, Hypnosis, Anesthesia, Amnesia (some), Convulsant and Anticonvulsant effects, Muscle Relaxation, Anxiolytic effects (impaired judgment, euphoria and loss of self control – at doses used for anxiolytic effects due to disinhibition), Depress respiration (if patient has pulmonary disease) Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Clinical Uses of Sedative and Hypnotic Drugs Katzung’s Basic & Clinical Pharmacology, 13th edition GABAA Modulators = Barbiturates and Benzodiazepines the Major Classes of Anxiolytic and Sedative-Hypnotic Drugs Binding Sites of Some GABAA Receptor Modulators Most drugs that act on GABAA receptors bind allosterically Barbiturates and benzodiazepines are positive modulators of GABAA receptor function. Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Effects of Benzodiazepines and Barbiturates on GABAA Receptors Both enhance GABAA receptor activation BUT binding sites, potencies and efficacies are different Midazolam – benzodiazepine Phenobarbital - barbiturate Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Effects of Benzodiazepines and Barbiturates on GABAA Receptors Both enhance GABAA receptor activation BUT binding sites, potencies and efficacies are different What is the mechanism of action of these drugs? Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy GABAA Modulators Vary in their Duration of Action FIX Trevor & Katzung’s Pharmacology Examination and Board Review, 9th edition Effects of Benzodiazepines and Barbiturates on GABAA Receptors Benzodiazepines • • • • • Allosteric binding site Potentiate Cl- flow Many have active metabolites Almost exclusively act on the CNS • v. high doses – NMJ block • Some after IV injection ➔coronary vasodilation ONLY facilitate effects of endogenous GABA ➔higher therapeutic index than barbiturates Brody’s Human Pharmacology Benzodiazepines Lippincott Illustrated Reviews: Pharmacology, 6th Edition Benzodiazepines Metabolism and Excretion * - active metabolite Brody’s Human Pharmacology Benzodiazepines – Duration of Action Lippincott Illustrated Reviews: Pharmacology, 6th Edition Duration of Action Can Predict the Likelihood of Withdrawal Effects of Benzodiazepines Short t1/2 Intermediate t1/2 Long t1/2 Lippincott Illustrated Reviews: Pharmacology, 6th Edition Duration of Action and Clinical Applications of Some Benzodiazepines Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Effects of Benzodiazepines and Barbiturates on GABAA Receptors Barbiturates Allosteric binding site – within channel Increase the conductance of GABAA to chloride ions • ALSO DIRECT GABAlike effects (partial agonists) • Inducers of CYP450 • Also affect own metabolism • Induce the rate-limiting step of heme biosynthesis ➔ Contraindicated in porphyria patients or those with family history of porphyria ➔ ALSO DIRECT GABAlike effects (partial agonists) ➔lower therapeutic index than benzodiazepines – PROBLEM OVERDOSE • • Brody’s Human Pharmacology Barbiturates Also Bind to AMPA/Kainate Glutamatergic Receptors Do you think that barbiturates INCREASE or DECREASE AMPA receptor activity? Barbiturates INHIBIT AMPA receptors  Inhibit the activation of a major excitatory receptor  Additional mechanism of suppressed neuronal excitability Lippincott Illustrated Reviews: Pharmacology, 6th Edition Duration of Action and Clinical Applications of Some Barbiturates Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Adverse Effects of Barbiturates Lippincott Illustrated Reviews: Pharmacology, 6th Edition To Summarize Effects of Benzodiazepines and Barbiturates on GABAA Receptors Benzodiazepines • • • • • Allosteric binding site Potentiate Cl- flow Many have active metabolites Almost exclusively act on the CNS • v. high doses – NMJ block • Some after IV injection ➔coronary vasodilation ONLY facilitate effects of endogenous GABA ➔higher therapeutic index than barbiturates Barbiturates Allosteric binding site – within channel Increase the conductance of GABAA to chloride ions • ALSO DIRECT GABAlike effects (partial agonists) • Inducers of CYP450 • Also affect own metabolism • Induce the rate-limiting step of heme biosynthesis ➔ Contraindicated in porphyria patients or those with family history of porphyria ➔ ALSO DIRECT GABAlike effects (partial agonists) ➔lower therapeutic index than benzodiazepines – PROBLEM OVERDOSE • • GABAA Modulators Vary in their Duration of Action FIX Trevor & Katzung’s Pharmacology Examination and Board Review, 9th edition Clinical Uses of Sedative and Hypnotic Drugs Katzung’s Basic & Clinical Pharmacology, 13th edition Summary of Sedatives and Hypnotic Drugs Katzung’s Basic & Clinical Pharmacology, 13th edition Newer Hypnotics – Similar to Benzodiazepines in Increasing Membrane Hyperpolarization Katzung’s Basic & Clinical Pharmacology, 13th edition Drug Overdose is a Problem BUT There is an Antagonist to Benzodiazepine Action Flumazenil is NOT a sedative hypnotic Katzung’s Basic & Clinical Pharmacology, 13th edition Sedatives and Hypnotics that DO NOT Act on GABA Receptors Melatonin Receptor Agonists Key Points for Role of Melatonin in Promoting Sleep • Melatonin synthesis • Inhibited by light • Promoted by darkness • Melatonin binds to melatonin receptors (MT1, MT2) • MT receptors • G-protein coupled (Gi/o) • Activation ➔  cAMP • Receptor functions • MT1 -  neuronal firing ➔ promote sleep • MT2 – circadian rhythm control An Orexin Receptor Antagonist - Sevorexant • • • • Key Points for Role of Orexins in Sleep Control Orexins = neuropeptides • Secretion is HIGH in states of wakefulness and arousal Orexins bind to orexin receptors (OX1, OX2) OX receptors • G-protein coupled (Gq/11) • Activation ➔  PLC activity ➔ Ca2+ in cytosol ➔  neuronal activity Orexin functions •  arousal, vigilance BUT also appetite control, reward, addictive behavior (suggested) Brody’s Human Pharmacology An Orexin Receptor Antagonist - Sevorexant • • • • Key Points for Role of Orexins in Sleep Control Orexins - neuropeptides • Inhibited by light • Promoted by darkness Orexins bind to orexin receptors (OX1, OX2) OX receptors • G-protein coupled (Gq/11) • Activation ➔  PLC activity ➔ Ca2+ in cytosol ➔  neuronal activity Orexin functions •  arousal, vigilance BUT also appetite control, reward, addictive behavior (suggested) Katzung’s Basic & Clinical Pharmacology, 13th edition Sedatives and Hypnotics that DO NOT Act on GABA Receptors Katzung’s Basic & Clinical Pharmacology, 13th edition Preview – Antiepileptic Drugs Simmons Pharmacology: An Illustrated Review Break GABA Receptors Clinically useful drugs target these Where do benzodiazepines bind on GABAA and how do they modulate GABA-induced receptor activity? Benzodiazepines ➔ Positive Allosteric Modulation of GABAA Receptors GABA bound Channel opens GABA + benzodiazepine bound  Frequency of channel opening benzodiazepine bound channel not affected Stahl’s, 4th Edition GABAA-Mediated Inhibition is Actually of Two Types Phasic = occurs in bursts triggered by synaptic increase of GABA release  synapse  GABAA – with α + γ subunits ➔ Benzodiazepines can bind Tonic = receptors capture GABA that has diffused away from synapse  extra synaptic  GABAA – with α + δ subunits ➔ Benzodiazepines CANNOT bind Stahl’s, 4th Edition GABA Receptors Clinically useful drugs target these Where do barbiturates bind on GABAA and how do they modulate GABA-induced receptor activity? Bind allosterically + keep channel open longer Why is GABAergic Neurotransmission an Important Pharmacological Target? • Pharmacological modulation of GABAegic neurotransmission affects: • Arousal and attention • Memory formation • Anxiety • Sleep • Muscle tone • Treatment of focal or widespread neuronal hyperactivity observed in • Epilepsy Effects of Benzodiazepines and Barbiturates on GABAA Receptors Benzodiazepines • • • • • Allosteric binding site Potentiate Cl- flow Many have active metabolites Almost exclusively act on the CNS • v. high doses – NMJ block • Some after IV injection ➔coronary vasodilation ONLY facilitate effects of endogenous GABA ➔higher therapeutic index than barbiturates Barbiturates Allosteric binding site – within channel Increase the conductance of GABAA to chloride ions • ALSO DIRECT GABAlike effects (partial agonists) • Inducers of CYP450 • Also affect own metabolism • Induce the rate-limiting step of heme biosynthesis ➔ Contraindicated in porphyria patients or those with family history of porphyria ➔ ALSO DIRECT GABAlike effects (partial agonists) ➔lower therapeutic index than benzodiazepines – PROBLEM OVERDOSE • • Summary of Sedatives and Hypnotic Drugs Katzung’s Basic & Clinical Pharmacology, 13th edition End of Small Recap Pharmacology of the Central Nervous System Treatment of Epilepsy Epilepsy and Seizures • Cause - often unclear • Can also develop as a result of brain damage after: • Stroke • Trauma • Infection • Tumor growth Epilepsy and Seizures • Epilepsy • • Group of chronic CNS disorders Abnormal discharges of CNS neurons • Discharge may have NO clinical manifestations • Can be focally limited or encompass the whole brain • Status epilepticus = prolonged seizures (>30min) or multiple seizures in succession without recovery of consciousness • Medical emergency – can lead to brain damage and even death • Treatment • Maintaining open airway • Provide oxygen • Glucose as a bolus • IV emulsion of diazepam (or rectal) Misdiagnosis and wrong medication can make seizures worse Types of Seizures Classification is not based on etiology but mostly on clinical manifestations Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Pathways of Seizure Propagation Focal seizure If affected region activity:  Confined to a cortical region serving a basic function e.g. motor or sensory + No change in the patient’s mental status ➔focal seizure without altered awareness. BUT  Serves complex function e.g. cognitive, linguistic etc ➔ focal seizures with altered awareness Partial seizures can evolve to to generalized tonic-clonic Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Pathways of Seizure Propagation Focal seizure If affected region activity:  Confined to a cortical region serving a basic function e.g. motor or sensory + No change in the patient’s mental status ➔focal seizure without altered awareness. BUT  Serves complex function e.g. cognitive, linguistic etc ➔ focal seizures with altered awareness Partial seizures can evolve to to generalized tonic-clonic Secondary generalized seizure  Begins in a focus BUT  Paroxismal activity spreads to subcortical areas ➔ Spread of activity to both hemispheres is synchronized by diffuse connections from the thalamus Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Generalized Seizures Can Also be of Primary Origin Primary generalized seizures (e.g. absence seizures)  Etiology  Abnormal synchronization between thalamic and cortical cells Or  Abnormal activity in neuronal networks that rapidly involve the bilateral hemispheres Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Epilepsy = disease of abnormal neuronal discharges Rationale behind epileptic drugs Inhibit abnormal neuronal discharges ➔ Prevent seizures from occurring How can you inhibit abnormal discharges? Hint: GABA = 1° inhibitory neurotransmitter in the CNS Glutamate = 1° excitatory neurotransmitter in the CNS Antiepileptic Drugs = Anticonvulsants = Antiepileptic drugs aim to inhibit the abnormal neuronal discharge rather than to correct the underlying cause Drugs that  GABA-mediated synaptic inhibition • Positive modulators GABAA Receptors • Phenobarbital i.e. barbiturates • Benzodiazepines • GABA mimetics e.g. progabide – GABAA agonist • Increase GABA synthesis MAYBE • Gabapentin – chemically related to GABA but not agonist to receptors – hypothesis is that is promotes synthesis of GABA although it is not a precursor of GABA • Inhibit GABA degradation • i.e. inhibit GABA-T e.g. vigabatrin • Inhibit GABA reuptake • i.e. inhibit GABA transporters (GATs) e.g. tiagabine Antiseizure Drugs Acting at Inhibitory GABAergic Synapses Katzung’s Basic & Clinical Pharmacology, 13th edition Summary of Antiepileptic Drugs Aimed at Increasing GABA-mediated synaptic inhibition Simmons Pharmacology: An Illustrated Review Epilepsy = disease of abnormal neuronal discharges Rationale behind epileptic drugs Inhibit abnormal neuronal discharges ➔ Prevent seizures from occurring How can you inhibit abnormal discharges? Hint: ✔GABA = 1° inhibitory neurotransmitter in the CNS Glutamate = 1° excitatory neurotransmitter in the CNS Antiepileptic Drugs = Anticonvulsants = Antiepileptic drugs aim to inhibit the abnormal neuronal discharge rather than to correct the underlying cause Drugs that  Glutamatergic Activity • Inhibitors of glutamatergic receptors • Felbamate – inhibits NMDA-type glutamate receptors • Perampamel – inhibits AMPA-type glutamate receptors Anticonvulsants Acting at Excitatory Glutamatergic Synapses Katzung’s Basic & Clinical Pharmacology, 13th edition Epilepsy = disease of abnormal neuronal discharges Rationale behind epileptic drugs Inhibit abnormal neuronal discharges ➔ Prevent seizures from occurring How can you inhibit abnormal discharges? Hint: ✔ GABA = 1° inhibitory neurotransmitter in the CNS ✔ Glutamate = 1° excitatory neurotransmitter in the CNS Action potential propagation is dependent on….? Voltage-gated Sodium Channels are Responsible for the Upstroke of Action Potentials and thus Action Potential Propagation Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Voltage-Gated Sodium Channels are Gated into Open, Closed and Inactivated States If we inhibit glutamate release we will inhibit hyperexcitability Katzung’s Basic & Clinical Pharmacology, 13th edition Antiepileptic Drugs = Anticonvulsants = Antiepileptic drugs aim to inhibit the abnormal neuronal discharge rather than to correct the underlying cause Drugs that  excitability • Inhibition of glutamate release – all about presynaptic Na+ channels • Phenobarbital – mechanism debated • Phenytoin – voltage-dependent Na+ channels – slows down their rate of recovery from inactivation • Lamotrigine – inhibits voltage-dependent Na+ channels in a voltagedependent and use-dependent manner Katzung’s Basic & Clinical Pharmacology, 13th edition Block of Lamotrigine of Voltage-Gated Sodium Channels is Voltage- and Use-Dependent Katzung’s Basic & Clinical Pharmacology, 13th edition Antiepileptic Drugs = Anticonvulsants = Antiepileptic drugs aim to inhibit the abnormal neuronal discharge rather than to correct the underlying cause Drugs that  excitability • Inhibition of glutamate release – all about presynaptic Na+ channels • Phenobarbital – mechanism debated • Phenytoin – voltage-dependent Na+ channels – slows down their rate of recovery from inactivation • Lamotrigine – inhibits voltage-dependent Na+ channels in a voltagedependent and use-dependent manner • Inhibit action potential propagation – postsynaptic voltage-dependent Na+ channels • voltage-dependent Na+ channels – slow down their rate of recovery from inactivation – inhibition of repetitive firing • Phenytoin + fosphenytoin (prodrug that is quickly converted to phenytoin in blood) • Carbamazepine Summary of Antiepileptic Drugs Katzung’s Basic & Clinical Pharmacology, 13th edition The Relationship between Phenytoin Dosage and Plasma Concentration is NOT Linear Lippincott Illustrated Reviews: Pharmacology, 7th Edition; Katzung’s Basic & Clinical Pharmacology, 13th edition The Relationship between Phenytoin and Oral Gabapentin Dosage and Plasma Concentration is NOT Linear  Most anticonvulsants - follow linear kinetics BUT  Phenytoin – metabolism gets saturated with increased doses ➔ shift from 1st to 0 order  Oral gabapentin – kinetics shift from 1st order to 0 BUT in the opposite direction because transporter necessary for absorption getting saturated Katzung’s Basic & Clinical Pharmacology, 13th edition Anticonvulsants Acting at Excitatory Glutamatergic Synapses Katzung’s Basic & Clinical Pharmacology, 13th edition Antiepileptic Drugs = Anticonvulsants = Antiepileptic drugs aim to inhibit the abnormal neuronal discharge rather than to correct the underlying cause Drugs that  excitability • Inhibition of glutamate release • Limiting Depolarization of the Terminal • Inhibition of Ca2+ entry – gabapentin + pregabalin – bind an auxiliary protein to voltage-gated Ca2+ channels ➔ inhibiting Ca2+ entry • Promoting repolarization – retigabine – a voltage-gated potassium channel OPENER ➔ promotes K+ EXIT • Inhibiting exocytosis of glutamatergic vesicles • Levetiracetam – binds a vesicular protein that promotes exocytosis (SV2A) ➔ vesicular release is INHIBITED Anticonvulsants Acting at Excitatory Glutamatergic Synapses Katzung’s Basic & Clinical Pharmacology, 13th edition Antiepileptic Drugs = Anticonvulsants = Antiepileptic drugs aim to inhibit the abnormal neuronal discharge rather than to correct the underlying cause Drugs that  excitability • Inhibition of T-type Ca2+ channels – i.e. inhibition of post-synaptic depolarization • Ethosuxamide – suspected mode of action (actually unknown) Summary of Antiepileptic Drugs Simmons Pharmacology: An Illustrated Review Antiepileptic Drugs = Anticonvulsants = Antiepileptic drugs aim to inhibit the abnormal neuronal discharge rather than to correct the underlying cause VALPROIC ACID (Divalproex = sodium valproate) •  voltage-dependent Na+ channels inactivation •  GABA-dependent synaptic inhibition by • blocking GABA-T (i.e. degradation) • or activating GAD (i.e. synthesis) • or by inhibiting GABA transporters (i.e. reuptake • DEBATE • Inhibits T-type Ca2+ channels • Inhibits NMDA-receptor activation Antiepileptic Drugs = Anticonvulsants = Antiepileptic drugs aim to inhibit the abnormal neuronal discharge rather than to correct the underlying cause VALPROIC ACID (Divalproex = sodium valproate) •  voltage-dependent Na+ channels inactivation •  GABA-dependent synaptic inhibition by • blocking GABA-T (i.e. degradation) • or activating GAD (i.e. synthesis) • or by inhibiting GABA transporters (i.e. reuptake • DEBATE • Inhibits T-type Ca2+ channels It is a potent inhibitor of histone deacetylase (HDAC) ➔changes the transcription of many genes It also inhibits CYP2C9, UDP-glucuronosyltransferase, epoxide hydrolase ➔  Drug-drug interaction risk In Utero Exposure to Valproate may Lead to Cognitive Dysfunction Lippincott Illustrated Reviews: Pharmacology, 7th Edition Valproic Acid in NOT the Only Broad Spectrum Anticonvulsant Katzung’s Basic & Clinical Pharmacology, 13th edition Summary of Antiepileptic Drugs Katzung’s Basic & Clinical Pharmacology, 13th edition Summary of Antiepileptic Drugs Aimed at Increasing GABA-mediated synaptic inhibition Simmons Pharmacology: An Illustrated Review Summary of Antiepileptic Drugs Aimed at Increasing GABA-Mediated Synaptic Inhibition Katzung’s Basic & Clinical Pharmacology, 13th edition Summary of Antiepileptic Drugs Aimed at Increasing GABA-Mediated Synaptic Inhibition Katzung’s Basic & Clinical Pharmacology, 13th edition Summary of Antiepileptic Drugs Aimed at Increasing GABA-Mediated Synaptic Inhibition Katzung’s Basic & Clinical Pharmacology, 13th edition Summary of Antiepileptic Drugs Aimed at Increasing GABA-Mediated Synaptic Inhibition Katzung’s Basic & Clinical Pharmacology, 13th edition Anticonvulsants Acting at Excitatory Glutamatergic Synapses Katzung’s Basic & Clinical Pharmacology, 13th edition Summary of Antiepileptic Drugs Katzung’s Basic & Clinical Pharmacology, 13th edition Summary of Antiepileptic DrugsDrugs Summary of Antiepileptic Simmons Pharmacology: An Illustrated Review Antiepileptic Drugs – Metabolized by CYP450 Lippincott Illustrated Reviews: Pharmacology, 6th Edition Adverse Effects of Antiepileptic Drugs Lippincott Illustrated Reviews: Pharmacology, 6th Edition Thank you