Pharmacology of Pain 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/ Recap Opiate Receptors Agonists and Antagonists Effects of Opioid...

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/ Recap Opiate Receptors Agonists and Antagonists 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 Opioid Receptor Agonists and Antagonists Agonists Mixed-Agonist Antagonists Antagonists 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 (normeperidine) – not analgesic BUT produces CNS excitation - Accumulates (if renal dysfunction) ➔ may lead to neurotoxicity 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 oxymorphone – metabolized by CYP2D6  often given orally in sustained-release version  PROBLEM – sustained-release tablets are sometimes crushed and ingested ➔ overdose and death 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 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 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 Opioid Receptor Agonists and Antagonists Agonists – Partial  partial = affinity but low intrinsic activity  buprenophrine  μ opioid receptor – high affinity but only partial agonist  decreases the severity of withdrawal symptoms 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 Primary Indications for Opioid Analgesics 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 Analgesic Agents 2. Treatment of Neuropathic Pain Peripheral Sensitization as a Pharmacological Target 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 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 Peripheral Sensitization is a Bit More Complex  Tanezumab – monoclonal antibody against NGF  Has been in clinical trials for years  Goal – treat pain that is resistant to other therapies  Goal – limit peripheral sensitization SUMMARY  It works – pain is reduced BUT serious safety concerns in every trial ➔Expression of NGF axis is altered in schizophrenia patients Peripheral Sensitization is a Bit More Complex Do you know any drugs that inhibit prostaglandin production? Nonsteroidal anti-inflammatory (NSAID) NSAIDs Nonsteroidal anti-inflammatory drugs (NSAIDs) Simmons Pharmacology: An Illustrated Review NSAIDs are inhibitors of Cox-1 and Cox-2  Inhibit both forms of cyclooxygenase (COX-1 and COX-2) ➔Inhibit - formation of prostaglandin H2  Critical step ➔ Inhibit prostaglandin metabolism  Anti-inflammatory effect - wanted But also block the physiological effects of COX-1 ➔ side effects COX-2 is induced by inflammation Inhibition is thought to lead to the analgesic, antipyretic, and antiinflammatory effects of aspirin and the other NSAIDs. Simmons Pharmacology: An Illustrated Review NSAIDs are inhibitors of Cox-1 and Cox-2  Inhibit both forms of cyclooxygenase (COX-1 and COX-2) ➔Inhibit - formation of prostaglandin H2  Critical step ➔ Inhibit prostaglandin metabolism  Anti-inflammatory effect - wanted But also block the physiological effects of COX-1 ➔ side effects Glucocorticoids (=class of corticosteroids) also inhibit prostaglandin (and leukotriene) production by inhibiting phospholipase A2 and COX2 (indirectly) Simmons Pharmacology: An Illustrated Review Key properties of NSAIDs Antipyretic effects are the result of  prostaglandins in the temperature control center in the hypothalamus NSAIDs Bind to the ACTIVE SITE Aspirin inhibits the COX by acetylating a single serine residue - an irreversible covalent modification - inactivates both COX-1 and COX-2 -> the binding is reversible BUT the modification is irreversible Other NSAIDs are competitive inhibitors of the cyclooxygenases. Uses of NSAIDs – General  Mild to moderate pain (e.g., dental, muscle, joint, and postoperative)  Inflammation and accompanying pain associated with diseases, such as rheumatoid arthritis (high doses)  Reduction of fever  Aspirin - treatment and prophylaxis of thrombosis (low doses). ➔ prevent myocardial infarction, stroke, and peripheral vascular thrombosis - Due to antithrombotic effects – used after  angioplasty  placement of stents bypass surgery The major difference between NSAIDs is in their pharmacokinetics Adverse Effects of NSAIDs Leukotrienes are proinflammatory mediators Simmons Pharmacology: An Illustrated Review NSAID - Contraindications Patients with:  Gastric ulcers - gastric irritation may aggravate ulcers  Asthmatics - can induce bronchospasm  Aspirin – may cause influenza-like illnesses in children or teenagers (up to 19 years of age)  increased risk of developing Reye syndrome in children with influenza or chickenpox - initially presents following a viral infection - Signs and symptoms - early - vomiting, lethargy, hyperventilation, and confusion - progress to severe mental state changes, coma, respiratory failure, multiple organ failure, and death - Treatment – supportive - mechanical ventilation (if necessary) - insulin ➔ glucose metabolism - corticosteroids ➔ brain swelling - and diuretics ➔ fluid loss NSAID - Contraindications Patients with:  Gastric ulcers - gastric irritation may aggravate ulcers  Asthmatics - can induce bronchospasm  Aspirin – may cause influenza-like illnesses in children or teenagers (up to 19 years of age)  increased risk of developing Reye syndrome in children with influenza or chickenpox  3rd trimester of pregnancy – may cause premature closure of the ductus arteriosus Salicylate Toxicity Mild toxicity  Nausea  Vomiting  Hyperventilation  Headache  Mental confusion  Dizziness  Tinnitus  Large doses cause severe intoxication  Restlessness  delirium  hallucinations  convulsions  coma  confusion  respiratory and metabolic acidosis  and death from respiratory failure In children – 10g aspirin can be fatal NSAIDs Participate In A Lot of Drug-Drug Interactions 80-90% of Aspirin is bound to Albumin Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Effects of NSAID-Mediated Inhibition of Prostaglandin Synthesis NSAIDs Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Effects of Aspirin Are Dose-Dependent Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Aspirin Elimination is of 0 Order Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Enzyme Selectivity of NSAIDs NSAIDs Lippincott’s Illustrated Reviews: Pharmacology, 7th edition NSAIDs - Summary Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Acetaminophen Acetaminophen  Not classified as an NSAID  Inhibits prostaglandin synthesis in the CNS ➔antipyretic and analgesic effects Peripherally inactivated ➔ Less effect on cyclooxygenase in periphery ➔Weak anti-inflammatory activity DOES NOT affect platelet function Uses:  Fever  Pain relief Especially in patients that have gastric complaints with NSAIDs BUT that doe not require the anti-inflammatory action of NSAIDs 1st choice in children Pharmacokinetics  Absorption – rapid  High 1st pass metabolism  Metabolized through – phase II reactions – 1° BUT CYP-mediated metabolism ➔ NAPQI formation NAPQI is TOXIC ➔ Drug-drug interactions can lead to hepatotoxicity Lippincott’s Illustrated Reviews: Pharmacology, 7th edition NSAIDs Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Neuropathic Pain Injury does not have to result in an axonal resection Scholz & Wolf Nature Neurosci. 2007 Overview of the Nociceptive Circuit Conduction from the periphery to spinal cord is via? C-fibers, Aδ, Aβ, silent C-fibers The fibers in blue are critical for nociception What is the difference between C-fibers and Aδ fibers? C-fibers – unmyelinated ➔ slower ➔ principle in perception of dull, diffuse pain Aδ–myelinated ➔ fast conduction ➔ principle in perception of sharp, welllocalized pain Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Neuropathic Pain Injury to the peripheral nerve ➔ Complex anatomical and biochemical changes in the nerve and spinal cord ➔ Induce spontaneous dysesthesias and allodynia ➔ Neuromas formed by nerve injury - ectopic activity ➔ Dorsal root ganglia – ectopic activity ➔ Reorganization of the dorsal horn (Aβ fiber activation) Neuropathic Pain  Does not necessarily depend on activation of small afferents BUT may be initiated by low-threshold sensory afferents (e.g. Aβ fibers) Examples of nerve injury that can lead to neuropathic pain nerve trauma or compression (carpal tunnel syndrome), chemotherapy-induced nerve damage, diabetes (i.e. diabetic neuropathy), post-herpetic state (i.e. shingles) Nerve Damage Causes a Cornucopia of Anatomical Changes Away from the Injury Site Anatomical changes are ALWAYS Activation of microglia – about a week after injury Scholz & Wolf Nature Neurosci. 2007 associated with changes in the axonal environment and as a result in changes in neuronal excitability Neuropathic Pain Nerve injury Axonal damage, crush, transection Wallerian degeneration Significant alteration of gene expression and sensitivity (in the ganglia) complex anatomical and biochemical changes in the nerve Goodmann & Gilman’s Pharmacology and Experimental Therapeutics, 14th Edition Inflammatory Changes Associated with Wallerian Degeneration Hyperemia and swelling in further infiltration of immune cells Scholz & Wolf Nature Neurosci. 2007 Degrade blood nerve barrier Increase of Neuregulin Expression Neuregulin  Expressed on axons, critical for myelination in development  Healthy adult – axonal expression negligible  Upon injury – neuregulin is reexpressed  acutely – induces Schwann cell dedifferentiation  later – promotes proliferation and remyelination Scholz & Wolf Nature Neurosci. 2007 Neuropathic Pain Nerve injury Demyelination (dedifferentiation of Schwann cells), infiltration of macrophages and other inflammatory cells Demyelination ➔ loss of neurotrophic support Bands of Bunger ➔ growth factor release, pathfinding signals Inflammatory cells and dedifferentiated Schwann cells ➔ cytokine release Red = negative signals Green = positive signals White = can be both positive and negative complex anatomical and biochemical changes in the nerve Goodmann & Gilman’s Pharmacology and Experimental Therapeutics, 14th Edition Modulation of Nociceptor Activity in Neuropathic Pain High concentration of extracellular ATP ➔ activation of P2X and P2Y receptors - if receptor on macrophage ➔ more cytokines released - if receptor is on nociceptor neurons ➔ nociceptor activation Scholz & Wolf Nature Neurosci. 2007 Modulation of Nociceptor Activity in Neuropathic Pain TTX-resistant Nav are potentiated ➔ Na+ influx ➔ Scholz & Wolf Nature Neurosci. 2007  excitability Important Note: The aforementioned mechanisms are well-studied and characterized in terms of nerve crush and nerve transection injuries Some of these mechanisms may be involved in chemotherapy-induced peripheral neuropathies The mechanisms behind diabetic neuropathies and pain are still largely unclear Why do we need to pay a special attention to neuropathic pain in our pharmacology class? One of the reasons: Nociceptive pain - usually is responsive to opioid analgesics BUT neuropathic pain - typically does not respond as well to opioid analgesics. Neuropathic Pain Nerve injury Demyelination (dedifferentiation of Schwann cells), infiltration of macrophages and other inflammatory cells Demyelination ➔ loss of neurotrophic support Bands of Bunger ➔ growth factor release, pathfinding signals Inflammatory cells and dedifferentiated Schwann cells ➔ cytokine release Red = negative signals Green = positive signals White = can be both positive and negative complex anatomical and biochemical changes in the nerve Goodmann & Gilman’s Pharmacology and Experimental Therapeutics, 14th Edition 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 Central Sensitization in Neuropathic Pain Ketamine – Blocks NMDAR Cohen & Mao TheBMJ 2014 Mechanisms of Central Sensitization in Neuropathic Pain Sodium Channel Blockers Carbamazepine + Oxcarbazepine – inhibition of activity – some clinical use Cohen & Mao TheBMJ 2014 Mechanisms of Central Sensitization in Neuropathic Pain Gabapentin and pregabalin Reduce neurotransmitter release Normally antiepileptic – BUT – also of important clinical use in neuropathic pain Cohen & Mao TheBMJ 2014 Mechanisms of Central Sensitization in Neuropathic Pain Zicontidine Blocks Ca2+ channels – severe pain – many side effects including hypotension and cognitive dysfunction Cohen & Mao TheBMJ 2014 Inhibitors of Tumor Necrosis Factor(TNFα) Etanercept, Infliximab, and Adalimumab - (monoclonal antibodies of soluble Fc fusion proteins) against TNF-α - bind to TNF-α + prevent it from attaching to receptor Key side effect - Increased susceptibility to bacterial and fungal infections IL-1 Antagonist - Anakinra - recombinant form of the human interleukin-1 receptor antagonist IL-1 Ra -blocks the actions of endogenous IL-1 -  IL-1-mediated inflammatory responses Pharmacokinetics – Given by daily subcutaneous injection Side effects - the same as TNF-α inhibitors i.e. injection site reactions + increased susceptibility to infections. Summary - Sites of Action of Analgesics Cohen & Mao TheBMJ 2014 Summary - Sites of Action of Analgesics Cohen & Mao TheBMJ 2014 Summary - Sites of Action of Analgesics Cohen & Mao TheBMJ 2014 Summary - Sites of Action of Analgesics Cohen & Mao TheBMJ 2014 Summary - Sites of Action of Analgesics Cohen & Mao TheBMJ 2014 Summary - Sites of Action of Analgesics Cohen & Mao TheBMJ 2014 Local and General Anesthetics What is Anesthesia? Anesthesia = lack of sensation What is the perfect anesthetic agent? The perfect anesthetic agent should cause/produce:  unconsciousness  analgesia  amnesia  muscle relaxation  NO side effects and toxicities What kind of anesthesia is being described here? General Anesthesia i.e. The reversible CNS depression that causes loss of stimulus perception + ➔ lack of response to external stimuli The Goals of Surgical Anesthesia Simmons Pharmacology: An Illustrated Review General Considerations in the Choice and Delivery of Anesthesia Optimal sedation level is a must The choice of anesthetic combination is determined by: Type and duration of the procedure  Characteristics of the patient (i.e. age, weight and physical condition, organ function, medical conditions)  What other medications is the patient taking (avoiding DDR is a MUST) Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Is there a perfect anesthetic agent? NO  the currently-available anesthetics are not ideal  each is prescribed in combination with other anesthetics and other medications to produce:  analgesia  amnesia  muscle relaxation What drugs are anesthetics combined with? Adjuncts to Anesthesia Aims of Anesthetic Adjuncts Treatment of Anxiety  Benzodiazepines (e.g. midazolam, diazepam)  additional benefit – anterograde amnesia  α2 agonists (e.g. clonidine, dexmedetomidine)  H1 antagonists (e.g. diphenhydramine) Analgesia  Opioids  BUT addictive ➔Aim – use less opioids and add other medications to help ➔ multimodal analgesia Adjuncts to opioids  NSAIDs (e.g. ketorolac, celecoxib)  BUT also anticoagulant ➔ CAUTION if patient suffering from coagulation problems + CAUTION – patients with peptic ulcers  Acetaminophen  CAUTION if hepatic insufficiency  Ketamine – NMDAR antagonist  GABA analogs (e.g. gabapentin, pregabalin) – pretreatment to reduce opioid use Prevention of postoperative nausea and vomiting (PONV) Control of GI motility, pH and tone Aims of Anesthetic Adjuncts Treatment of Anxiety Analgesia Prevention of postoperative nausea and vomiting (PONV) Usually Given at the End of Surgery  5-HT3 receptor antagonists  given towards end of surgery  CAUTION – patients with long QT intervals  Promethazine – anticholinergic + antihistaminic  BUT sedation, delirium, and confusion esp. in the elderly Usually Given at the Beginning of Surgery  Glucocorticoids (e.g. dexamethasone)  Aprepitant - neurokinin-1 antagonist Usually Given at the Before Surgery  Scopolamine – mAChR antagonist  transdermally for patients with history of PONV  CAUTION – anticholinergic actions in the CNS Control of GI motility, pH and tone Aims of Anesthetic Adjuncts Treatment of Anxiety Analgesia Prevention of postoperative nausea and vomiting (PONV) Control of GI motility, pH and tone  gastric acidity (esp.. obstetrics + patients with acid reflux) H2-receptor antagonists + proton pump inhibitors (for quick relief – nonparticulate antacids (e.g. sodium citrate)  prokinetic drugs ➔  GI motility + gastric emptying +  tone of lower esophageal sphincter – e.g. metoclopramide (D2 antagonist but also 5-HT3 weak antagonist + 5-HT4 agonist) Summary of the Functions of Adjuncts to Anesthesia Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Summary of the Functions of Adjuncts to Anesthesia Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Levels of Sedation  Depend on:  the dose  the patient and his/her drug response Hallmarks that predict escalation from one level to the next BUT escalation from one level to the next is often subtle and unpredictable Lippincott’s Illustrated Reviews: Pharmacology, 7th edition General Anesthesia is Divided in Stages General Anesthesia is Divided in Stages Stage I - Analgesia  Analgesia  Amnesia and loss of pain awareness – as stage II is approached  Consciousness of pain - as stage II is approached Stage II - Excitement  Disinhibition  Delirium  Maybe combative behavior   blood pressure and respiration  risk of laryngospasm ➔ Stage should be as short as possible ➔ Short-acting IV opiates given before induction of anesthesia Lippincott’s Illustrated Reviews: Pharmacology, 6th edition General Anesthesia is Divided in Stages Stage III – Surgical Anesthesia  CNS is further depressed  Loss of muscle tone and reflexes  Relaxation of skeletal muscles ➔ loss of spontaneous movement  Respiration and blood pressure – under control ➔ Perfect for surgery ➔ Needs to be prolonged as much as necessary Stage IV – Medullary Depression/Paralysis  SEVERE cardiovascular and respiratory depression ➔ Ventilation and/or circulation must be supported mechanically and pharmacologically to AVOID DEATH Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Anesthetic Techniques • Minor procedures → conscious sedation: - IV agents & local anesthetics • More extensive surgical procedures – IV agents → anesthesia induction – Inhaled anesthetics (with or without intravenous agents) to maintain an anesthetic state – Neuromuscular blockers → muscle relaxation IV agent Inhaled anesthetic “Balanced anesthesia” Anesthetic drugs SHOULD Have Rapid Onset & Offset • “Minute to minute” control is the “holy grail” of general anesthesia • Allows rapid adjustment of the depth of anesthesia • Ability to awaken the patient promptly at the end of the surgical procedure • Requires inhalation anesthetics and short-acting intravenous drugs Glossary:  Induction of anesthesia = time from anesthetic administration to development of unconsciousness  Depends on rate of distribution of anesthetic to the brain  Recovery from anesthesia = time from discontinuation of anesthetic administration to return of consciousness and protective reflexes  Depends on rate of REdistribution of anesthetic from the brain Drugs used for General Anesthesia The Goals of Surgical Anesthesia Simmons Pharmacology: An Illustrated Review Stages of Anesthesia Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4th edition General Considerations in the Choice and Delivery of Anesthesia Optimal sedation level is a must The choice of anesthetic combination is determined by: Type and duration of the procedure  Characteristics of the patient (i.e. age, weight and physical condition, organ function, medical conditions)  What other medications is the patient taking (avoiding DDR is a MUST) Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Is there a perfect anesthetic agent? NO  the currently-available anesthetics are not ideal  each is prescribed in combination with other anesthetics and other medications to produce:  analgesia  amnesia  muscle relaxation What drugs are anesthetics combined with? Adjuncts to Anesthesia Aims of Anesthetic Adjuncts Treatment of Anxiety  Benzodiazepines (e.g. midazolam, diazepam)  additional benefit – anterograde amnesia  α2 agonists (e.g. clonidine, dexmedetomidine)  H1 antagonists (e.g. diphenhydramine) Analgesia  Opioids  BUT addictive ➔Aim – use less opioids and add other medications to help ➔ multimodal analgesia Adjuncts to opioids  NSAIDs (e.g. ketorolac, celecoxib)  BUT also anticoagulant ➔ CAUTION if patient suffering from coagulation problems + CAUTION – patients with peptic ulcers  Acetaminophen  CAUTION if hepatic insufficiency  Ketamine – NMDAR antagonist  GABA analogs (e.g. gabapentin, pregabalin) – pretreatment to reduce opioid use Prevention of postoperative nausea and vomiting (PONV) Control of GI motility, pH and tone Aims of Anesthetic Adjuncts Treatment of Anxiety Analgesia Prevention of postoperative nausea and vomiting (PONV) Usually Given at the End of Surgery  5-HT3 receptor antagonists  given towards end of surgery  CAUTION – patients with long QT intervals  Promethazine – anticholinergic + antihistaminic  BUT sedation, delirium, and confusion esp. in the elderly Usually Given at the Beginning of Surgery  Glucocorticoids (e.g. dexamethasone)  Aprepitant - neurokinin-1 antagonist Usually Given at the Before Surgery  Scopolamine – mAChR antagonist  transdermally for patients with history of PONV  CAUTION – anticholinergic actions in the CNS Control of GI motility, pH and tone Aims of Anesthetic Adjuncts Treatment of Anxiety Analgesia Prevention of postoperative nausea and vomiting (PONV) Control of GI motility, pH and tone  gastric acidity (esp.. obstetrics + patients with acid reflux) H2-receptor antagonists + proton pump inhibitors (for quick relief – nonparticulate antacids (e.g. sodium citrate)  prokinetic drugs ➔  GI motility + gastric emptying +  tone of lower esophageal sphincter – e.g. metoclopramide (D2 antagonist but also 5-HT3 weak antagonist + 5-HT4 agonist) Summary of the Functions of Adjuncts to Anesthesia Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Summary of the Functions of Adjuncts to Anesthesia Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Levels of Sedation  Depend on:  the dose  the patient and his/her drug response Hallmarks that predict escalation from one level to the next BUT escalation from one level to the next is often subtle and unpredictable Lippincott’s Illustrated Reviews: Pharmacology, 7th edition General Anesthesia is Divided in Stages General Anesthesia is Divided in Stages Stage I - Analgesia  Analgesia  Amnesia and loss of pain awareness – as stage II is approached  Consciousness of pain - as stage II is approached Stage II - Excitement  Disinhibition  Delirium  Maybe combative behavior   blood pressure and respiration  risk of laryngospasm ➔ Stage should be as short as possible ➔ Short-acting IV opiates given before induction of anesthesia Lippincott’s Illustrated Reviews: Pharmacology, 6th edition General Anesthesia is Divided in Stages Stage III – Surgical Anesthesia  CNS is further depressed  Loss of muscle tone and reflexes  Relaxation of skeletal muscles ➔ loss of spontaneous movement  Respiration and blood pressure – under control ➔ Perfect for surgery ➔ Needs to be prolonged as much as necessary Stage IV – Medullary Depression/Paralysis  SEVERE cardiovascular and respiratory depression ➔ Ventilation and/or circulation must be supported mechanically and pharmacologically to AVOID DEATH Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Stages of Anesthesia Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4th edition Anesthetic Techniques • Minor procedures → conscious sedation: - IV agents & local anesthetics • More extensive surgical procedures – IV agents → anesthesia induction – Inhaled anesthetics (with or without intravenous agents) to maintain an anesthetic state – Neuromuscular blockers → muscle relaxation IV agent Inhaled anesthetic “Balanced anesthesia” Anesthetic drugs SHOULD Have Rapid Onset & Offset • “Minute to minute” control is the “holy grail” of general anesthesia • Allows rapid adjustment of the depth of anesthesia • Ability to awaken the patient promptly at the end of the surgical procedure • Requires inhalation anesthetics and short-acting intravenous drugs Glossary:  Induction of anesthesia = time from anesthetic administration to development of unconsciousness  Depends on rate of distribution of anesthetic to the brain  Recovery from anesthesia = time from discontinuation of anesthetic administration to return of consciousness and protective reflexes  Depends on rate of REdistribution of anesthetic from the brain Drugs used for General Anesthesia Inhalation Anesthetics = Volatile, halogenated hydrocarbons AND nitrous oxide Effects:   Cerebrovascular resistance ➔ Brain perfusion   Pulmonary Effects  Bronchodilation   respiratory drive   pulmonary vasoconstriction in response to hypoxia ➔ hypoxic regions of the lungs have HIGH vascular resistance BUT better oxygenated regions have low vascular resistance ➔ Pulmonary blood flow – redirected to lung areas of HIGH oxygenation Mechanism of Action of Inhalation Anesthetics - Activate K+ channels - Block Na+ channels - Disrupt membrane lipids ➔ All general anesthetics ➔ neuronal firing threshold ➔  neuronal activity Promiscuous Receptor Agonist Theory suggests that anesthetics may act at:  GABAR -  sensitivity to GABA  NMDAR – inhibit  & other receptors Why do we need yet another theory? Modulation of GABA Binding by Inhalation Anesthetics Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Pharmacokinetics of Volatile Anesthetics and Nitrous Oxide are Related to their Potency Pressure I. InhaledPartial anesthetics ❖ The concentration of a gas in a mixture of gases is proportional to the partial pressure Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4th edition Pharmacokinetics of Inhalation Anesthetics I. Inhaled anesthetics ❖ The concentration of a gas in a mixture of gases is proportional to the partial pressure ❖ Inverse relationship between blood/gas solubility (i.e. the blood/gas partition coefficient) & rate of induction ❖ Why? Halothane is MORE soluble in blood ➔ it will take longer for the halothane partial pressure in blood to reach the same level as it is in the alveoli - Since the concentration in the brain CANNOT rise faster than the concentration in the blood ➔ halothane will reach the brain SLOWER NOTE: Size of the blood rectangle is indicative of the relative solubility of the gas in the compartment - Small rectangle = less soluble Nitrous oxide solubility in blood < HALOTHANE SOLUBILITY IN BLOOD ➔ Rate of induction achieved by halothane will be much SLOWER than nitrous oxide Blood/Gas Partition Coefficient of Inhaled Anesthetics The Meyer-Overton rule  The HIGHER the partition coefficients the HIGHER the potency  Potency = 1/MAC Lippincott’s Illustrated Reviews: Pharmacology, 7th edition; Golan, Armstrong&Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4th edition Potency of Anesthetic Gases is Defined by their Minimal Alveolar Concentrations (MACs) MAC (minimum alveolar anesthetic concentration) = the alveolar concentration required to eliminate the response to a standardized painful stimulus in 50% of patients i.e. the ED50 of inhaled anesthetics Which one is the most potent? - Halothane Which one is the least potent? – Nitrous Oxide Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Potency of Anesthetic Gases is Defined by their Minimal Alveolar Concentrations (MACs) MAC (minimum alveolar anesthetic concentration) = the alveolar concentration required to eliminate the response to a standardized painful stimulus in 50% of patients i.e. the ED50 of inhaled anesthetics A Word about Halothane  Introduced in 1950s + was the true innovation of pharmacology of anesthesia BUT too many side effects including - Halothane-induced hepatitis – can range from mild to moderate to full blown hepatotoxicity Lippincott’s Illustrated Reviews: Pharmacology, 6th + 7th edition Potency of Anesthetic Gases is Defined by their Minimal Alveolar Concentrations (MACs) MAC (minimum alveolar anesthetic concentration) = the alveolar concentration required to eliminate the response to a standardized painful stimulus in 50% of patients i.e. the ED50 of inhaled anesthetics Can MAC be altered? YES Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Potency of Anesthetic Gases is Defined by their Minimal Alveolar Concentrations (MACs) MAC (minimum alveolar anesthetic concentration) = the alveolar concentration required to eliminate the response to a standardized painful stimulus in 50% of patients i.e. the ED50 of inhaled anesthetics MAC can be Increased by:  HYPERthermia  Increased CNS catecholamine levels – i.e. any drug that can do this  Chronic ethanol abuse MAC can be Decreased by:  HYPOrthermia  Pregnancy  Sepsis  Acute intoxication  Age  α2 agonists  IV anesthetics – concurrently used Factors Influencing the Rate of Induction of Inhalation Anesthetics Golan, Armstrong & Armstrong Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4th edition Changes in Alveolar Blood Concentrations During Induction and Recovery Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Inhalation Anesthetics – the Volatile, Halogenated Hydrocarbons Isoflurane, Desflurane, Sevoflurane Key points • Predominant action - Systemic vasorelaxation ➔ dose-dependent hypotension – can be treated with direct-acting vasoconstrictors (e.g. phenylephrine) • Isoflurane + Desflurane – pungent odor ➔ Stimulates respiratory reflexes ➔NOT used for induction BUT not a problem with sevoflurane ➔ sevoflurane – used for induction esp.. in children • Relative blood solubilities determine use  High blood solubility ➔ equilibrium will be delayed ➔ avoided in short procedures (e.g. isoflurane)  Low blood solubility ➔ equilibrium reached quickly ➔ rapid onset + recovery ➔ preferred in short procedures (e.g. desflurane + sevoflurane) Inhalation Anesthetics – Nitrous oxide Effects and Use: • Better analgesic than halogenated agents ➔ can be used alone for analgesia • Unlike halogenated agents  Does NOT decrease blood pressure  Does NOT depress respiration  Does NOT produce surgical levels of anesthesia (except – in very high doses + inadequate oxygenation ➔ NOT used alone for anesthesia BUT in combination Side effects  Can cause diffusion hypoxia ➔ ALWAYS administered with 30 to 35% oxygen ALSO 100% oxygen given at cessation of treatment until nitrous oxide is removed form the lungs by expiration • Long-term exposure to trace concentrations ➔ May cause pernicious anemia ➔ May cause increased incidence of spontaneous abortions Inhalation Anesthetics – Summary Effects  All produce unconsciousness, amnesia, and analgesia – to various extents ALSO to various extents   Blood pressure  Depress respiration   Intracranial pressure (except - nitrous oxide) Critical side effects that require aggressive treatment – both are rare  Hyperkalemia  Malignant hyperthermia (most common with halothane but can be caused by all)  Inhaled anesthetic ➔ oxidative metabolism of skeletal muscles ➔ oxygen consumption ➔CO2 build up + loss of temperature regulatory capacities ➔rapid  in body temperature ➔ collapse and death if untreated  Treatment - Dantrolene A Practice of Anesthesia for Infants and Children, 6th edition Great Comparison Table In Your Book Lippincott’s Illustrated Reviews: Pharmacology, 7th edition Better in the Older Edition Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Summary of Inhalation Agents Simmons Pharmacology: An Illustrated Review Intravenous Anesthetics Pharmacological Properties of Parenteral Anesthetics Duration of action of single IV doses of anesthetics is similarly short Duration of action is determined by the redistribution of the drugs away from their active sites BUT in prolonged infusions – things are very different Goodman & Gilman’s Pharmacological Basis of Therapeutics, 13th edition Redistribution and Termination of Effects of Parenteral Anesthetics Initial distribution to the brain is due to the high blood flow to the brain  Redistribution ➔Drug levels in brain ➔ Anesthesia stops before full elimination of the drug from the body Simmons Pharmacology: An Illustrated Review Context-Sensitive Half-Time of General Anesthetics Drug half-times and duration of action of general anesthetics after prolonged infusion are dependent on:  Rate of drug redistribution  Amount of drug accumulation in fat  Rate of drug metabolism ➔Complex combination of factors = context-sensitive half-time How can we determine the half-life then? Goodman& Gilman’s Pharmacological Basis of Therapeutics, 13th edition Context-Sensitive Half-Time of General Anesthetics Drug half-times and duration of action of general anesthetics after prolonged infusion are dependent on:  Rate of drug redistribution  Amount of drug accumulation in fat  Rate of drug metabolism ➔Complex combination of factors = context-sensitive half-time  To determine this phenomenon we need to know the context  What is the total dose given?  What is the length of administration (time)?  Ketamine – low accumulation  Diazepam + Thiopental – HIGH accumulation Goodman& Gilman’s Pharmacological Basis of Therapeutics, 13th edition Intravenous Anesthetics - Propofol Mechanism of action  Unclear  Blocks Na+ channels   GABA-mediated neuronal inhibition via GABAA receptors Pharmacokinetics  Metabolized rapidly by the liver  Renally excreted Uses and Considerations for General Anesthesia  Rapid induction of anesthesia (30-40sec) and recovery  Poor analgesic ➔ supplementation with opiate needed  Antiemetic properties ➔  chances of PONV Side effects  Hypotension (due to decreased vascular resistance) • May contributes to excitatory phenomena, such as muscle twitching, spontaneous movement, yawning + hiccups Intravenous Anesthetics - Ketamine Mechanism of action  It is an open channel blocker  Antagonist of NMDA receptors (a channel blocker) BUT not only  Blocks HCN1 channels – i.e. neuronal hyperpolarization-activated cationic currents blocked  nAChR channel blocker  Agonist and potentiator of μ and δ opioid receptors  Also affects  the nitric-oxide (NO)–cyclic guanosine-mono-phosphate (cGMP) system  AMPA receptors  metabotropic glutamate receptors (mGluR)  and L-type Ca2+ channels  reduces in cholinergic neuromodulation  increases release of aminergic neuromodulators (dopamine and noradrenaline) BUT NOT ONLY Intravenous Anesthetics - Ketamine The multitude of Ketamine Effects Sleigh et al. Trends in Anesthesia and Critical Care 2014 Intravenous Anesthetics - Ketamine Uses in General Anesthesia  It is a dissociative anesthetic ➔ patient feels dissociated from the environment  At anesthetic doses - causes  Catatonia  Amnesia  Analgesia  Induction and maintenance of general anesthesia BUT is usually AVOIDED due to side effects Side effects:  Hallucinations  Disorientation Intravenous Anesthetics – the Barbiturates Thiopental, Thiamylal, and Methohexital Key Points on Use • Induction of anesthesia BUT anesthesia maintained with an inhalation agent • Remain in the body for a long time Very lipophilic – accumulate in adipose tissue and little is available for metabolism by the liver at any given time • Limited analgesic effects Side effects • Respiratory and cardiovascular depression ➔ These are not preferred – methohexital is still used for electroconvulsive therapy Distribution Reminder - Thiopental  Ultra short-lived GABA mimetic  Increases inhibitory potential of GABA receptors  Perfusion rates are critical for anesthetic use Figure modified from: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th edition Distribution Reminder - Phases of Distribution 1st Phase 2nd Phase Heart Liver Kidney Brain Muscle Most viscera Skin Adipose Tissue 1st few minutes Smaller, well-perfused organs 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 • • Intravenous Anesthetics – the Benzodiazepines Diazepam, Midazolam, and Lorazepam Key Points on Anesthesia Use • Used as premedications to produce sedation and amnesia • Some cardiovascular depressant effects • Potential respiratory depressants (esp.. if administered IV) • May produce temporary anterograde amnesia ➔ need to repeat treatment information, etc to the patient after drug wears off • Metabolized by the liver • t1/2 – varies (DDR - erythromycin may prolong midazolam t1/2) Intravenous Anesthetics – the Opioids Fentanyl, Sufentanil and Remifentanil - the most commonly used Key Points on Anesthesia Use • Analgesics ➔ commonly used • The meperidine analogs – faster analgesia onset and more potent than morphine - preferred • Not good in producing amnesia • Cause hypotension and respiratory depression • Cause nausea and vomiting Intravenous Anesthetics – the Neuromuscular Blockers Cisatracurium, Mivacurium, Pancuronium, Rocuronium, Succinylcholine, and Vecuronium Key Points on Anesthesia Use • Key in anesthesia as block muscle responses • Facilitate intubation • nAChR competitive antagonists EXCEPT 1 – Which one? Sugammadex  Binds rocuronium and vecuronium ➔ Traps blocker ➔ Inhibition terminator + reversal agent • Popular – rapid, effective of shallow and profound NMJ blockade Intravenous Anesthetics – Other Drugs Etomidate • Potentiates GABAA - at high concentrations actually can induce currents in the absence of GABA (but still bound at an allosteric site) Also – centrally acting α2 agonist BUT inhibits 11-β-hydroxylase (needed for steroidogenesis) ➔ USED ONLY in patients with cardiac dysfunction or in acute, critical patients • Rapid induction + short-acting • Benefit - NO effects on the heart and systemic vascular resistance BUT decreased plasma cortisol and aldosterone levels Dexmedetomidine • α2 receptor agonist • Effects: sympatholytic, anxiolytic (blunt cardiovascular responses), sedative, analgesic  Blunts – emergence delirium in children • Can actually decrease the requirement for volatile anesthetics Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Local Anesthetics Methods of Local Anesthesia Administration Simmons Pharmacology: An Illustrated Review Local Anesthetics are either Ester- or Amide-Linked Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Reminder - Voltage-Gated Ion Channels e.g. voltage-gated Na+ Channel No physiological ligands - still drug targets e.g. lidocaine – local anesthetic blocks channel pore Katzung Pharmacology: Examination & Board Review, 11th edition Mechanisms of Action of Local Anesthetics  Lipophilic so readily diffuse inside the cell  Block the channel from inside  Na+ entry is prevented  Main differences between the different types are in the duration of action  Action is terminated upon diffusion of drug away from site of action  Metabolized by the liver – both types, esters – also metabolized in plasma by estherases Simmons Pharmacology: An Illustrated Review Summary of Local Anesthetics PABA = para-aminobenzoic acid - there are individuals that have sensitivity to PABA + -> can develop allergic reactions Lippincott’s Illustrated Reviews: Pharmacology, 7th edition