Preliminary_20231107_Glutamatergic and GABAergic Neurotransmission_Sedatives_Hypnotics.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(MAOIs)  Block dopamine breakdown ➔ May exaggerate effects (hypertensive crisis and hyperpyrexia) ➔ MAOIs should be withdrawn at least 2 weeks prior to l-DOPA administration  Anticholinergics - may slow gastric emptying Lippincott Illustrated Reviews: Pharmacology, 7th Edition 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 • 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) 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 Pharmacology of the Central Nervous System Opioids and Opioid Receptors Opiate Receptors Agonists and Antagonists But before we delve into that… STUDY HELP CNS – Neurotransmitter Receptors and Effectors Simmons Pharmacology: An Illustrated Review Opiate Receptors Agonists and Antagonists But before we delve into that… What is pain? And is it beneficial? Pain = the end perceptual consequence of neural processing (CNS and PNS) of particular sensory information How do we treat pain?  Effective treatment always depends on the cause  Is it acute or is it chronic?  Is it nociceptive or neuropathic?  Nociceptive – e.g. moderate arthritic pain – usually response to non-opioid analgesics e.g. NSAIDs  Neuropathic – e.g. due to cancer chemotherapy – usually treated with TCAs, anticonvulsants, reuptake inhibitors (NE and 5-HT)  Opioids – severe acute pain (e.g. post-OP), chronic malignant or nonmalignant pain Overview of the Nociceptive Circuit Noxious stimulus Activation of peripheral terminal Action potentials travel to the dorsal horn Synapse in the dorsal horn ➔ signal relayed to the CNS neurons CNS neurons – send message to the cortex Ascending signals can be modulated by descending signals Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Pain Mechanisms and Pathways as Pharmacological Targets The type of perceived pain depends on the brain locations that the information (impulses) is relayed to by CNS neurons i.e. pain depends on the CNS target  Localized target (e.g. postcentral gyrus small, specific area) ➔ short, sharp, well-localized pain Broad target (e.g. multiple cortical areas) ➔ dull, poorly localized pain Simmons Pharmacology: An Illustrated Review Normal Pain Perception vs Allodynia vs Hyperalgesia Allodynia = normally innocuous stimuli are perceived as painful Hyperalgesia = high-intensity stimuli are perceived as MORE painful and LONGER lasting If termed  ‘primary’ – i.e. pain is perceived at the site of injury – then mostly caused by peripheral sensitization, i.e. thresholds and conduction of peripheral neurons is altered Cohen & Mao TheBMJ 2014  ‘secondary’ – i.e. pain is no longer perceived as localized but still intense – mostly caused by central sensitization, i.e. sensory processing is altered Mechanisms of Tissue Injury-Evoked Nociception  Tissue injury or local inflammation (e.g., local skin burn, rheumatoid joint) ➔an ongoing pain state – i.e. burning, throbbing, aching ➔May lead to hyperalgesia = pain evoked by otherwise innocuous or mildly aversive stimuli (e.g. tepid bathwater on a sunburn; moderate extension of an injured joint) Facilitation vs Inhibitory Pathways  Facilitation = pathways that enhance pain perception  Inhibitory = pathways that inhibit pain perception Goodmann & Gilman’s Pharmacology and Experimental Therapeutics, 14th Edition Mechanisms of Tissue Injury-Evoked (Nociceptive) Pain  Reasons for hyperalgesia:  Release of cytokines, prostaglandins, bradykinin, H+ ions at injury site ➔ Can activate Aδ and C fibers ➔ Peripheral sensitization = reduction of the activation threshold of high-threshold afferents  Activation of spinal facilitory cascades ➔ Greater output to the brain for any given input Spinal facilitation = the key to hyperalgesia Goodmann & Gilman’s Pharmacology and Experimental Therapeutics, 14th Edition Mechanisms of Peripheral Sensitization Phosphorylation of receptors ➔ ion flux upon activation Phosphorylation of Na+ channels ➔ ion flux ➔channel activation threshold Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy How are nociceptive stimuli detected? Specific Nociceptive Stimuli Act on Specific Channels on the Terminals of Afferent Sensory Fibers in the Periphery Piezzo channel for innocuous stimulus <16° (TRM8) or >42° (TRPV) Active research is focused on developing drugs that will act specifically on these receptors Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Chemosensitive Transduction Receptors  ATP - concentration in the extracellular space is normally very low BUT if cells rapture due to injury ➔ Millimolar (mM) concentrations of ATP Kinin peptides (kinins) – produced from kininogens when cleaved by kallikrein serine proteases  Inflammation or tissue damage ➔ cleavage of kininogens ➔ kinins produced  Healthy tissue ➔ NO cleavage of kininogens ➔ no kinins Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Overview of the Nociceptive Circuit Conduction from the periphery to the spinal cord is via? C-fibers, Aδ, Aβ, silent C-fibers What type of channels are critical for action potential propagation? Nav Reason for research into the benefits of TTX in the therapy of certain types of pain Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Overview of the Nociceptive Circuit Conduction from the periphery to spinal cord is via? C-fibers, Aδ, Aβ, silent C-fibers What type of channels are critical for action potential propagation? Nav Nav1.7 mutations  Loss-of-function ➔ congenital INsensitivity to pain  Gain-of-function ➔ Hyperexcitability of nociceptors ➔ Severe burning pain - spontaneous - response to mild heat = 1° erythromelalgia Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Mechanisms of Peripheral Sensitization Phosphorylation of receptors ➔ ion flux upon activation Phosphorylation of Na+ channels ➔ ion flux ➔channel activation threshold Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Neurotransmission in the Dorsal Horn Neurotransmitters – glutamate + the neuropeptides - substance P, calcitonin generelated peptide (CGRP) glutamate neuropeptides Fast postsynaptic depolarization SLOW postsynaptic depolarization Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Overview of the Nociceptive Circuit Noxious stimulus Activation of peripheral terminal Action potentials travel to the dorsal horn Synapse in the dorsal horn ➔ signal relayed to the CNS neurons CNS neurons – send message to the cortex Ascending signals can be modulated by descending signals Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Inhibitory Regulation of Neurotransmission in the Dorsal Horn Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Inhibitory Regulation of Neurotransmission in the Dorsal Horn Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy How do we treat pain?  Effective treatment always depends on the cause  Is it acute or is it chronic?  Is it nociceptive or neuropathic?  Nociceptive – e.g. moderate arthritic pain – usually response to non-opioid analgesics e.g. NSAIDs  Neuropathic – e.g. due to cancer chemotherapy – usually treated with TCAs, anticonvulsants, reuptake inhibitors (NE and 5-HT)  Opioids – severe acute pain (e.g. post-OP), chronic malignant or nonmalignant pain Opiate Receptors Agonists and Antagonists Pain Mechanisms and Pathways as Pharmacological Targets Simmons Pharmacology: An Illustrated Review Opioids Exhibit Analgesic Functions on Both Ascending and Descending Pathways Ascending Nociceptive Circuit Descending Inhibitory Pathway Katzung’s Basic & Clinical Pharmacology, 14th Edition The Receptors Lippincott’s Illustrated Reviews: Pharmacology, 7th edition The Receptors Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Effects of Opioid Receptor Signaling Opioid Receptors δ μ κ These are G-protein coupled receptors Ligand binding leads to:  Postsynaptic K+ conductance (hyperpolarization)  Postsynaptic activation  Presynaptic Ca2+ conductance Presynaptic neurotransmitter release Inhibition of adenylyl cyclase ➔cAMP Effect on nociception still unclear Actions Mediated by Opiate Receptors Simmons Pharmacology: An Illustrated Review The Ligands Endogenous Opioids are Synthesized as Precursors (Propeptides) and Cleaved  Endogenous opioids i.e. opioid peptides  all synthesized as propeptides  all propeptides need to be cleaved to release the active opioid ligands  all share the same Nterminus (YGGFM/L) Receptors - Ligands  μ – enkephalins and βedorphins  δ – enkephalins and βedorphins  k – dynorphins Simmons Pharmacology: An Illustrated Review Localization of endogenous opioids  Endorphins - the pituitary gland  Enkephalins and dynorphins - throughout the nervous system and the gut What are the effects of Endogenous Opioids? Functions of endogenous opioids  Endorphins  principal - pain reduction  additional - euphoria, cause the release of sex hormones, and modulate appetite ‘runner’s high’ – sense of euphoria and well-being - due to endorphin release during prolonged/strenuous  Enkephalins and dynorphins  pain regulation and modulation Exogenous Ligands i.e. Opioid Receptor Agonists The Opioids Can be Classified as Opioids Can ALSO be Classified according to Structure or according to Function Can you interpret/discuss the findings below? Morphine was applied to a knockout mouse of the μ opioid receptor The results were: no analgesia or adverse effects ➔ Morphine is a specific agonist for the μ opioid receptor Morphine and Related Compounds Receptor Specificity of Opioids Morphine and Related Compounds  Morphine = the standard for comparison among opioids  Many semisynthetic compounds - made by modifying the morphine molecule e.g. Diacetylmorphine (heroin), hydromorphone, oxymorphone, oxycodone, and hydrocodone Mechanisms of action Act at all opiate receptors BUT with the highest affinity at µ receptors Activation of µ receptors ➔ spontaneous activity of neurons in the GI and CNS  in the CNS – morphine acts on areas known to be involved in:  respiration  pain perception  mood emotion Morphine and Related Compounds AC = Adenylyl cyclase GIRK = G-protein–activated inwardly rectifying potassium channel Kv = voltage-gatedpotassium channel PKA = protein kinase A PLA2 = phospholipase A2 Brody’s Human Pharmacology Morphine and Related Compounds Morphine = the standard for comparison among opioids e.g. Diacetylmorphine (heroin), hydromorphone, oxymorphone, oxycodone, and hydrocodone Mechanisms of action Activation of µ receptors ➔ spontaneous activity of neurons in the GI and CNS Why?  Opioid receptors – G-protein-coupled  Gi or Go ➔cAMP  K+ currents  Ca2+ currents ➔ Hyperpolarization ➔  neurotransmitter release Overall - selective inhibition of the excitatory inputs to neurons involved in transmitting information about noxious stimuli without changing the responses to other types of stimuli How is Morphine Metabolized? Morphine is Metabolized by Glucuronidation in the Liver M6G – active metabolite M3G – inactive metabolite Are drug-drug interactions of concern with morphine? Not metabolized by CYP450 – so no need to worry about inducers or inhibitors BUT glucoronidation – so need to be aware if patient is taking antibiotics Why? Simmons Pharmacology: An Illustrated Review The Multitude of Effects of Morphine Morphine Pharmacokinetics  Absorption - readily absorbed from the gastrointestinal (GI) tract (but absorption is unpredictable), nasal mucosa, and lungs.  Bioavailability of oral preparation ranges from 15 to 50% due to firstpass metabolism in the liver – so if given orally (extended release preparations)  Metabolized by glucuronide conjugation  Excreted as a glucuronide conjugate in the urine  Diacetylmorphine (heroin) is rapidly deacetylated in the liver to monoacetylmorphine, which is further deacetylated to morphine. General Characteristics of Morphine and Related Compounds  Acute relief of pain (symptomatic treatment only)  Chronic treatment of pain  Antitussive actions i.e. cough suppressants  Useful in diarrhea to produce constipation  Small amounts of opium tincture or paregoric are ingested.  of particular use following ileostomy or colostomy and in diarrhea and dysentery Primary Indications for Opioid Analgesics - Overview Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Efficacies of Opioids Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Are Potency and Efficacy Equivalent? i.e. Is the Most Potent Drug also the Most Efficacious? Side Effects of Morphine and Related Compounds  Nausea  Constipation – due to  GI motility +  tone of intestinal smooth muscles  Mental cloudiness  Dysphoria  Vomiting  Increased biliary pressure  HypOtension and bradycardia – ONLY LARGE DOSES  Sweating and vasodilation – due to  histamine release  Pupillary miosis SEVERE RESPIRATORY DEPRESSION IN OVERDOSE ➔ DEATH in OVEROSE Morphine should not be used in head trauma patients – may cause build up in CSF as causes dilation of cerebral blood vessels Morphine should only be used in asthmatics with CAUTION – causes bronchoconstriction Labor – morphine ➔  strength, duration and frequency of contraction ➔ prolongs 2nd stage of labor Side Effects of Morphine and Related Compounds Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Opioids Can Induce Androgen Deficiency  Opioid-induced androgen deficiency The Clinical Symptoms Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Opioid Side Effects Actually Depend on Length of Use Important Contraindications Opioids should be avoided in certain patients:  Asthmatics – cause bronchoconstriction  Patients with lung disease – cause respiratory depression  Patients with head injury because mental clouding, vomiting, and miosis may interfere with neurologic assessment of the patient Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Opioid Receptor Agonists and Antagonists Agonists Mixed-Agonist Antagonists Let’s start with the agonists Antagonists Codeine Codeine  Naturally occurring opioid  Weak analgesic compared to morphine  action due to conversion to morphine by CYP2D6 NOTE: CYP2D6 – subject to polymorphisms and patient idiosyncrasy Problem: ultra-rapid metabolizers ➔ faster codeine➔morphine conversion ➔morphine ➔ may lead to overdose and toxicity e.g. some children that have tonsillectomy and/or adenoidectomy + given codeine have experienced life-threatening reparatory depression  Uses: mild to moderate pain - usually combined with acetaminophen ALSO  Antitussive – at low doses that are insufficient to cause analgesia BUT Dextromethorphan – preferred for cough suppression due to  potential for abuse Hydromorphone and Hydrocodone  Both orally-active  Both semisynthetic Hydromorphone  Analog of morphine  4-7x >potency than morphine (when both given orally)  Less accumulation of active metabolites than morphine ➔ preferred for patients with renal disease and dysfunction Hydrocodone  Analog of codeine  Analgesic efficacy - <than hydromorphone BUT equal to morphine  Uses: moderate to sever pain – usually combined with acetaminophen or ibuprofen - antitussive (again not preferred) Synthetic Opioids Methadone Pharmacodynamics  μ agonist  antagonist of the N-methyl-D-aspartate (NMDA) receptor  norepinephrine and serotonin reuptake inhibitor Pharmacokinetics  Good absorption after oral administration – unlike morphine  Distribution – very lipophilic + rapid distribution BUT slow redistribution (➔elimination – slow)  Metabolism – NO active metabolites - liver, multiple CYPs involved -> rate varies + patient idiosyncrasy is a factor ➔ CAUTION – many drug-drug interactions possible  Excretion – feces (almost entirely)  t1/2 = 12-40hrs but even 150hrs BUT analgesia only lasts 4-8hrs  Time to reach Css = 35hrs to 2 weeks ➔ doses can be adjusted only possible in 5-7days Synthetic Opioids Methadone Uses:  Nociceptive and neuropathic pain  Opioid withdrawal  Less euphoria than morphine  Longer duration of action than morphine  Withdrawal syndrome  milder  longer duration Problems and Contraindications:  Just like morphine – can produce physical dependence  Less neurotoxic than morphine (no active metabolites)  Potentially interacts with cardiac potassium channels  Can prolong to QT interval  Can cause torsades de pointes arrhythmia ➔ ECG monitoring (baseline and routine) - recommended Synthetic Opioids Meperidine Pharmacodynamics  Synthetic  Structurally unrelated to morphine.  κ agonist + some μ agonist activity  ALSO anticholinergic effects ➔  incidence of delirium  Normeperidine - active metabolite - potentially neurotoxic - renal excretion ➔ DANGER patients with renal dysfunction - symptoms of high levels of normperidine - delirium, hyperreflexia, myoclonus and seizures Pharmacokinetics  Short duration of action  Metabolized to normeperidine – renally excreted active metabolite with potential for neurotoxicity Uses  Short-term (<48hrs) management of pain with CAUTION Synthetic Opioids Meperidine Contraindications  Elderly patients since have  kidney function  Patients with renal disease, insufficiency and failure  Respiratory-compromised patients (if dysfunction is preexistent)  Patients with hepatic insufficiency Clinically-relevant Drug-Drug Interactions  With MAOIs - should be avoided in patients that are currently taking those or have recently taken them  SSRIs ➔ serotonin syndrome Synthetic Opioids Fentanyl  Meperidine analog Pharmacokinetics:  Highly lipophilic ➔ rapid onset + fast distribution  Short duration of action (15-30min)  Usual routes of administration – IV, intrathecal, epidural, transdermal patches (formulation – reservoir for prolonged release and offset (12hrs)  Metabolism – CYP3A4 ➔ prone to clinically relevant drug-drug interactions with inhibitors Uses:  Analgesia – 100x more potent than morphine  Postoperative pain  Labor  Note: In both cases combined with local anesthetics  Anesthesia – as causes sedation  Severe pain – as transdermal patch  Cancer-related breakthrough pain in opioid tolerant patients – in transmucosal and nasal formulations Contraindication: Opioid-naïve patients Synthetic Opioids Sufentanil, alfentanil, remifentanil, and carfentanil  Meperidine analogs – related to fentanyl  Differ in potency and pharmacokinetics  Used for: surgeries requiring anesthesia due to sedative + analgesic effects BUT NOT carfentanil  Key points Potency  Sufentanil + carfentanil - MORE potent than fentanyl  Carfentanil – 100x MORE potent than fentanyl ➔NOT USED clinically BUT USED to lace heroin ➔ CAUSE of opioid-related death  Alfentanil + remifentanil - LESS potent than fentanyl Opioid Receptor Agonists and Antagonists Opioid Receptor Agonists and Antagonists Agonists – Only a Summary  similar to morphine in terms of effects and side effects  meperidine and analogs – no antitussive or constipating actions  meperidine – better absorbed than morphine  metabolite – not analgesic BUT produces CNS excitation - Accumulates ➔ may lead to renal dysfunction  fentanyl = meperidine analog – 80-100x more potent than morphine  sufentanil = meperidine analog – 6000x more potent than morphine  codeine – metabolized into morphine by CYP2D6 ➔ weaker than morphine  oxycodone and oxymorophone – metabolized by CYP2D6 (oxycodone also CYP33A4)  often given orally in sustained-release version  PROBLEM – sustained-release tablets are sometimes crushed and ingested ➔ overdose and death Opioid Receptor Agonists and Antagonists Opioid Receptor Agonists and Antagonists Opioid Receptor Agonists and Antagonists Agonists – Partial  partial = affinity but low intrinsic activity  buprenorphine  μ opioid receptor – high affinity but only partial agonist  decreases the severity of withdrawal symptoms What is a partial agonist?  Binds to opioid receptors  Agonist with low intrinsic activity (lower than that of full agonist) (or agonist that activates some but not all downstream effector cascades) ➔Efficacy lower than full agonist Can a partial agonist be more potent than a full agonist? Partial Agonists Buprenorphine Potent partial agonist at the μ receptor BUT antagonist at the κ receptors  Since very potent + high affinity  can displace morphine (and other less potent agonists) from the receptors Pharmacokinetics:  Very lipophilic  Route of administration - sublingual, transmucosal, buccal, parenteral, subdermal, and transdermal  Long duration of action – due to very high affinity for opioid receptors Partial Agonists Buprenorphine Uses:  Moderate to severe pain  Medication-assisted treatment of opioid addiction – when given sublingually or transdermally  provides long suppression of opioid withdrawal BUT if addict is actively taking opioids – can quickly displace them from opioid receptors ➔ exaggerate withdrawal  high potency - can displace opioids from receptors  low efficacy – lower risk or respiratory depression (BUT NOT if combined with benzodiazepines + other CNS depressants) - less euphoria i.e. ‘ceiling effect’ Preferred over methadone because:  Methadone – complicated pharmacokinetics ➔ can only be given by licensed practitioners (clinics) ALSO  withdrawal symptom severity +  duration of symptoms than methadone Partial Agonists Buprenorphine Side Effects:  If respiratory depression – that cannot be easily reversed by naloxone  Decreased (BUT also rarely increased) blood pressure  Nausea + dizziness  Sometimes prolongs QT interval (but may be clinically insignificant – DEBATE) – still risk evaluation should be performed Opioid Receptor Agonists and Antagonists Opioid Receptor Agonists and Antagonists Mixed-Agonist Antagonists = agonists for some but antagonists for other receptors of the same class Effects – often depend on the previous exposure to opioids of the patient  in opioid-naïve patients – usually show agonist activity and are used as analgesics  pentazocin  agonist for κ, but weak antagonist for μ and δ  analgesia – primary use (BUT not for severe pain), sedation and respiratory depression  may block morphine-induced analgesia  less euphoria than morphine  CANNOT antagonize morphine-induced respiratory depression  may cause withdrawal symptoms in a morphine user  CAUTION - patients with angina or coronary artery disease – blood pressure increase possible Other Mixed Agonists-Antagonists Nalbuphine and butorphanol      Like pentazocine – limited use in treating chronic pain Like pentazocine – limited ceiling effect for respiratory depression Less psychotomimetic effects than pentazocine Nalbuphine – no cardiac effects + no increase in BP Butorphanol – also as nasal spray but abuse likely Other Analgesics Tapentadol  Agonist at the μ opioid receptor  Inhibitor of norepinephrine reuptake Pharmacokinetics: Metabolized to INactive metabolites by glucuronidation Uses:  Moderate to severe acute and chronic pain  Also including neuropathic pain associated with diabetic peripheral neuropathy Caution:  To be avoided if patient received MAOIs within 2weeks Other Analgesics Tramadol  Agonist at the μ opioid receptor (centrally acting)  Inhibits reuptake of norepinephrine and serotonin - WEAKLY Pharmacokinetics:  Metabolized to active metabolite by CYP2D6  active metabolite – higher affinity for μ opioid receptors Uses:  Moderate to severe pain Caution: Tramadol toxicity = symptoms – CNS excitation + seizures  CANNOT BE EASILY REVERSED BY naloxone  Can cause anaphylactic reactions  Should NOT be used in patients with a history of seizures To be avoided if patient received MAOIs within 2weeks, TCAs  Drug-drug interactions with CYP inducers and inhibitors Opioid Receptor Agonists and Antagonists Opioid Receptor Agonists and Antagonists  e.g. naloxone, naltrexone, namefene Antagonists  competitive inhibitors  highest affinity for μ OR  induce withdrawal to opioid addicts ➔ addict must be opioid free for >1week  naloxone + namefene  IV  namefene – longer duration  treat opioid poisoning  Natrexone – also oral  Tested for alcohol addiction treatment  longer effect than naloxone (single oral dose can block heroin effect for 24hrs, single IM dose can block heroin effect for 30days  can cause hepatoxoticity -> monitor hepatic function Summary Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Primary Indications for Opioid Analgesics Simmons Pharmacology: An Illustrated Review Actions Mediated by Opiate Receptors Simmons Pharmacology: An Illustrated Review Opioids - Summary Drug-Drug Interactions of Opioids Opioid action is potentiated by these drugs  phenothiazines (i.e. antipsychotics)  monoamine oxidase inhibitors (MAOIs)  tricyclic antidepressants Some phenothiazines  sedative effects of morphine while  analgesic effects Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Tolerance and dependence are characteristics of the opioid drugs The Rewarding Properties of Opiates  MOR = μ opioid receptor  μ opioid receptor agonists  Ca2+ influx  K+ efflux ➔excitability of - GABAergic interneurons ➔ GABA-mediated inhibition ➔  excitability, i.e. outflow from ventral pallidum ➔REWARD Goodmann & Gilman’s Pharmacology and Experimental Therapeutics, 14th Edition Opioid Withdrawal Syndrome Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Opioid Withdrawal – Severity Comparison All 3 drugs have equal doses in this figure Naltrexone and other antagonists – also used in addiction treatment – prevent relapses Lofexidine or clonidine – α2 agonists also ameliorate withdrawal symptoms Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Opioid Withdrawal Syndrome Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Pharmacology of the Central Nervous System 1. Anti-inflammatory, Antipyretic and