Cns/Pain Introduction to Central Nervous System Pharmacology PDF

CNS/PAIN Introduction to Central Nervous System Pharmacology Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved.  The Blood-Brain Barrier  Impedes entry of drugs into the brain  Passage across the blood-brain barrier limited to lipi...

CNS/PAIN Introduction to Central Nervous System Pharmacology Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved.  The Blood-Brain Barrier  Impedes entry of drugs into the brain  Passage across the blood-brain barrier limited to lipid-soluble drugs  Protein-bound or highly ionized drugs cannot cross Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 2  Adaptation of the CNS to Prolonged Drug Exposure  Decreased side effects: When CNS drugs are taken chronically, the intensity of the side effects may decrease, but the therapeutic effects remain undiminished  Example:  Morphine is taken to control pain  Nausea is a common side effect early on  Treatment continues, nausea diminishes, and analgesic effects persist 3 Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved.  Adaptation of the CNS to Prolonged Drug Exposure  Tolerance  Decreased response occurring during the course of prolonged drug use  Physical dependence  State in which abrupt discontinuation of drug use will precipitate a withdrawal syndrome 4 Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved.  Analgesics and Opioids  Analgesics are drugs that relieve pain without causing the loss of consciousness  Opioids are the most effective pain relievers available Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 5  Endogenous Opioid Peptides  Three families of peptides  Enkephalins  Endorphins  Dynorphins Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 6  Opioid Receptors  Three main classes of opioid receptors  Mu receptors: Analgesia, respiratory depression, euphoria, sedation, and physical dependence  Kappa receptors: Analgesia and sedation; kappa activation may underlie psychotomimetic effects seen with certain opioids  Delta receptors Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 7  Classification of Drugs That Act as Opioid Receptors  Agonist, partial agonist, or antagonist  Pure opioid agonists  Agonist-antagonist opioids  Pure opioid antagonists Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 8  Pure Opioid Agonists  Activate mu receptors and kappa receptors  Can produce analgesia, euphoria, sedation, respiratory depression, physical dependence, constipation, and other effects  Morphine: Strong opioid agonists and moderate to strong opioid agonists  Codeine: Moderate to strong agonists Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 9  Agonist-Antagonist Opioids  Pentazocine, and buprenorphine  When administered alone, produce analgesia  If administered with a pure opioid agonist, can antagonize analgesia caused by the pure agonist Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 10  Pure Opioid Antagonists  Naloxone [Narcan]: Prototype of the pure opioid antagonists  Antagonists at mu and kappa receptors  Do not produce analgesia or any of the other effects caused by opioid agonists  Reversal of respiratory and central nervous system (CNS) depression caused by overdose with opioid agonists Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 11  Basic Pharmacology of the Opioids  Strong opioid agonists  Morphine  Other strong opioid agonists  Moderate to strong opioid agonists  Agonist-antagonist opioids Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 12  Morphine  Source  Seedpod of the poppy plant  Overview of pharmacologic actions  Pain relief  Drowsiness  Mental clouding  Anxiety reduction  Sense of well-being Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 13  Morphine  Overview of pharmacologic actions  Respiratory depression  Constipation  Urinary retention  Orthostatic hypotension  Emesis  Miosis  Cough suppression  Biliary colic  Tolerance and physical dependence  Euphoria/Dysphoria Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 14  Morphine  Toxicity  Clinical manifestations  Classic triad  Coma  Respiratory depression  Pinpoint pupils  Treatment  Ventilatory support  Antagonist: Naloxone [Narcan]  General guidelines  Monitor vital signs before giving  Give on a fixed schedule Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 15  Morphine  Therapeutic use: Relief of pain  Relieves pain without affecting other senses (for example, sight, touch, smell, and hearing)  No loss of consciousness  Relieve pain by mimicking the actions of endogenous opioid peptides, primarily at mu receptors Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 16  Morphine  Pharmacokinetics  Administered by several routes: oral, intramuscular, intravenous, subcutaneous, epidural, and intrathecal  Not very lipid-soluble  Does not cross blood-brain barrier easily  Only small fraction of each dose reaches site of analgesic action Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 17  Morphine  Tolerance and physical dependence  Physical dependence  Abstinence syndrome with abrupt discontinuation  About 10 hours after last dose, the initial reaction occurs and includes yawning, rhinorrhea, and sweating  Progresses to violent sneezing, weakness, nausea, vomiting, diarrhea, abdominal cramps, bone and muscle pain, muscle spasms, and kicking movements  Lasts 7 to 10 days if untreated  Withdrawal is unpleasant but not lethal, as it may be with CNS depressants Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 18  Morphine  Abuse liability  Precautions  Decreased respiratory reserve  Pregnancy  Labor and delivery  Head injury  Other precautions Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 19  Morphine  Drug interactions  CNS depressants  Anticholinergic drugs  Hypotensive drugs  Monoamine oxidase inhibitors  Agonist-antagonist opioids  Opioid antagonists  Other interactions Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 20  Other Strong Opioid Agonists  Fentanyl [Duragesic, Abstral, Actiq, Fentora, Onsolis, Lazanda, Subsys]  100 times the potency of morphine  Formulations given via three routes  Parenteral  Surgical anesthesia  Transdermal [Duragesic]  Patch: Heat acceleration  Iontophoretic system: Needle-free  Transmucosal  Lozenge on a stick [Actiq]  Buccal film [Onsolis]  Buccal tablets [Fentora]  Sublingual tablets [Abstral]  Sublingual spray [Subsys] Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 21  Other Strong Opioid Agonists  Alfentanil and sufentanil  Remifentanil  Meperidine  Short half-life  Interacts adversely with several other drugs  Toxic metabolite accumulation  Methadone  Treatment for pain and opioid addicts Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 22  Other Strong Opioid Agonists  Hydromorphone (Dilaudid)  Morphine derivative. Much more potent  relative potency of hydromorphone to morphine is 7.5:1  Given to those with severe pain  Highly addictive Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 23  Moderate to Strong Opioid Agonists  Similar to morphine in most respects  Produce analgesia, sedation, and euphoria  Can cause the following:  Respiratory depression, constipation, urinary retention, cough suppression, and miosis  Can be reversed with naloxone  Different from morphine  Produce less analgesia and respiratory depression than morphine  Somewhat lower potential for abuse Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 24  Moderate to Strong Opioid Agonists  Codeine  Actions and uses  10% converts to morphine in liver  Pain and cough suppression  Preparations, dosage, and administration  Usually oral (formulated alone or with aspirin or acetaminophen)  30 mg produces same effect as 325 mg of acetaminophen Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 25  Moderate to Strong Opioid Agonists  Oxycodone  Analgesic actions equivalent to those of codeine  Long-acting analgesics  Immediate-release  Controlled-release [OxyContin]  Abuse: Crushes and snorts or injects medication  2010 OP formulation much harder to crush and does not dissolve into an injectable solution to decrease risk of abuse Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 26  Moderate to Strong Opioid Agonists  Hydrocodone (Vicodin)  Most widely prescribed drug in the United States  Combined with aspirin, acetaminophen, or ibuprofen Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 27  Agonist-Antagonist Opioids  Pentazocine (Talwin)  Agonist on Kappa, Antagonist on Mu  Limited resp. depression  Can precipitate withdrawal in addicted pts.  Buprenorphine  7-day patch: Butrans  Sublingual film: Suboxone Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 28  Dosing Guidelines  Assessment of pain  Pain status should be evaluated before opioid administration and about 1 hour after  Dosage determination  Opioid analgesics must be adjusted to accommodate individual variation  Dosing schedule  As a rule, opioids should be administered on a fixed schedule  Avoiding withdrawal Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 29  Clinical Use of Opioids  Balance the need to provide pain relief with the desire to minimize abuse  Minimize fears about the following:  Physical dependence  Addiction Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 30  Clinical Use of Opioids  Patient-controlled analgesia  Patient-controlled analgesia devices  Drug selection and dosage regulations  Comparison of patient-controlled analgesia with traditional intramuscular therapy  Multiple intramuscular injections: Painful to the patient; cause negative side effects, including bruising and hematoma formation  Patient education  Family education Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 31  Opioid Antagonists  Principal uses:  Treatment of opioid overdose and relief of opioid-induced constipation  Reversal of postoperative opioid effects  Reversal of neonatal respiratory depression  Management of opioid addiction Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 32  Naloxone  Mechanism of action  Competitive antagonist  Pharmacologic effects  Pharmacokinetics Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 33  Naloxone  Therapeutic uses  Reversal of opioid overdose  Drug of choice with pure opioid agonist overdose  Titrated cautiously with physical dependence  Reversal of postoperative opioid effects  Titrated to achieve adequate ventilation and to maintain pain relief  Reversal of neonatal respiratory depression  Opioids given during labor and delivery may cause respiratory depression in neonate Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 34  Naloxone  Preparations, dosage, and administration  Preparations and routes  Opioid overdose  Postoperative opioid effects  Neonatal respiratory depression Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 35  Nonopioid Centrally Acting Analgesics  Relieve pain by mechanisms largely or completely unrelated to opioid receptors  Do not cause respiratory depression, physical dependence, or abuse  Not regulated under the Controlled Substances Act Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 36  Nonopioid Centrally Acting Analgesics  Tramadol [Ultram]  Suicide risk  Clonidine [Duraclon] Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 37  Tramadol (Ultram)  Mechanism of action  Combination of opioid and nonopioid mechanisms  Therapeutic use: Moderate to moderately severe pain  Adverse effects: Sedation, dry mouth  Drug interactions  CNS depressants  Abuse liability  Suicide  Preparations, dosage, and administration  Immediate-release and extended-release Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 38  Clonidine  Treatment of hypertension and relief of severe pain  Mechanism of pain relief  Alpha2-adrenergic agonist  Analgesic use  Used in combination with opioid analgesics  Adverse effects  Cardiovascular: Severe hypotension, rebound hypertension, and bradycardia  Contraindications Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 39