Opoid agonist and antagonits

WHO analgesic ladder Pain Pain persists Pain persists 03/11/101 WHO analgesic ladder Pain Pain persists Pain persists or increases or increases 3. Strong opioid ± non-opioid ± adjuvant 2. Weak opioid ± non-opioid ± adjuvant 1. Non-opioid ± adjuvant 9

Classes of opoids agonists

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Opioid analgesics All drugs in this category act by binding to specific Opioid receptors in CNS to produce effects that mimic the action of naturally occurring substances, called endogenous opioid peptides or endorphins. Exert their major effect by interacting with Opioid receptor in the CNS, and in other places such as GI tract and urinary bladder. Opioids cause hyperpolarization of nerve cells, inhibiting nerve firing, and presynaptic inhibition of transmitter release. Morphine causes analgesia, and patients treated with morphine are still aware of the presence of pain, but sensation is not unpleasant.

Opioid Analgesics: Indications Main use: to alleviate moderate to severe pain Cough centre suppression Treatment of diarrhea Balanced anaesthesia

Opioid Analgesics: Side Effects Euphoria CNS depression Nausea and vomiting Respiratory depression Urinary retention Diaphoresis and flushing Pupil constriction (miosis) Constipation Itching

Repeated use of Morphine Department of Pharmacology, DSMA Repeated use of Morphine Psychological dependence Physical dependence Tolerance Withdrawal syndrome Hyperalgesia???????

Tolerance/Dependence/Addiction – Physiologic phenomenon resulting in progressive decline in potency of an opioid with continued use. Addiction – Psychological & behavioralsyndrome manifested by drug seeking behavior, loss of control of drug use, and continued use despite adverse effects. Dependence – Physiologic state characterized by withdrawal symptoms upon abrupt discontinuation/ reduction of narcotic therapy. • Abstinence syndrome • Independent of tolerance

Withdrawl Reactions Acute Action Withdrawl Sign Analgesia Respiratory Depression Euphoria Relaxation and sleep Tranquilization Decreased blood pressure Constipation Pupillary constriction Hypothermia Drying of secretions Flushed and warm skin Withdrawl Sign Pain and irritability Hyperventilation Dysphoria and depression Restlessness and insomnia Fearfulness Increased blood pressure Diarrhea Pupillary dilation Hyperthermia Lacrimation, runny nose Chilliness and “gooseflesh”

Pregnancy and elderly If acetaminophen is insufficient, opioids are considered acceptable during pregnancy provided they are given for a short duration. Chronic opioid use can result in fetal dependence, premature delivery and growth retardation. In elderly Opioid analgesics have an increased likelihood of more profound adverse effects as well as prolonged durations of action. Therefore it is best not to select an opioid. If it is necessary, reduced doses must be utilized.

Subclass Mechanism of Action Effects Clinical Applications Pharmacokinetics, Toxicities Strong opioid agonists    Morphine Strong -receptor agonists Analgesia relief of anxiety sedation slowed gastrointestinal transit Severe pain adjunct in anesthesia (fentanyl, morphine) pulmonary edema (morphine only) maintenance in rehabilitation programs (methadone only) First-pass effect duration 1–4 h except methadone, 4–6 h Toxicity: Respiratory depression severe constipation addiction liability convulsions   Methadone   Fentanyl   Hydromorphone, oxymorphone: Like morphine in efficacy, but higher potency    Meperidine: Strong agonist with anticholinergic effects    Sufentanil, alfentanil, remifentanil: Like fentanyl but shorter durations of action  Partial agonists    Codeine Less efficacious than morphine Like strong agonists weaker effects Mild-moderate pain cough Like strong agonists, toxicity dependent on genetic variation of metabolism

Opioids Strong opioids Weak opioids Oxycodone Codeine Morphine 03/11/101 Opioids Strong opioids Oxycodone Morphine Methadone Fentanyl Mepiridine Weak opioids Codeine Tramadol 17

Morphine Opioids induce sleep, and in clinical situations when pain is present and sleep is necessary, morphine may be used to supplement the sleep-inducing properties of hypnotic agents Morphine relieves diarrhea by decreasing the motility and increasing the tone of the intestinal smooth muscles Morphine produce a powerful sense of euphoria and well-being. Morphine is also used in the treatment of acute pulmonary edema, intravenous morphine is dramatically relieve dyspnea cause by pulmonary edema associated with left ventricular failure.

Kidney Morphine has 2 biologically active metabolites, morphine-6- glucuronide and morphine-3-glucuronide. Morphine-6-glucuronide binds to the opioid receptor and is believed to contribute to the effects of the parent compound. Morphine-3-glucuronide does not bind to the receptor and is believed to contribute in some cases to adverse effects such as myoclonus and confusion. Usually, the metabolites are considered a clinical issue only when their concentrations in the blood are likely to fluctuate differently than the concentration of the parent compound. This can occur during renal insufficiency,

Hydromorphone may be preferred over morphine for patients with decreased renal clearance, to preempt the potential for toxicity from morphine metabolite accumulation.

(Mepiridine, pethidine) 03/11/101 (Mepiridine, pethidine) Repetitive dosing leads to accumulation of the toxic metabolite normeperidine (normeperidine) Norpethidine accumulation causes CNS hyper-excitability, subtle mood changes, Tremors, Multifocal myoclonus, Seizures Common with repeated large doses, eg 250 mg per day. It is renally cleared, and use of meperidine in patients with kidney disease is not recommended. 25

Mepiridine Obstetric labor Shivering

Methadone NMDA receptors blocking Monoaminergic reuptake transporters. Treat difficult to treat pain, especially when morphine failed. Widely used in opioids abuse. why?????

Source: NSW Department of Health (2007) NSW Drug and Alcohol Withdrawal Clinical Practice Guidelines 25

Tramadol Analgesic action mechanism Not fully understood Weak affinity for -opioid receptor Inhibition of norepinephrine reuptake → 2-adrenoreceptor activation → act synergistically with tramadol’s opioid receptor activation → analgesia Advantage Less respiratorpsychomotor recoveryy depression, nausea, vomiting, constipation Rapid Moderate pain treatment : as effective as morphine Severe pain treatment : less effective than morphine

Peripherally Acting Opioid Opioid receptor – outside central nerve system Peripherally acting opioid agonist → analgesia without CNS side effect Loperamide -opioid receptor agonist Not cross blood-brain barrier Treatment : inflammation-induced hyperalgesia Relieve diarrhea

PARTIAL AGONISTS AND MIXED AGONIST–ANTAGONISTS Partial agonists bind to the opioid receptor, but have less intrinsic activity than full agonists Drugs that stimulate one receptor but block another are termed mixed agonist–antagonists. The effects of these drugs depend on previous exposure to opioids. In individuals who have not received opioids (naïve patients), mixed agonist–antagonists show agonist activity and are used to relieve pain. In the patient with opioid dependence, the agonist–antagonist drugs may show primarily blocking effects (that is, produce withdrawal symptoms).

Buprenorphine Buprenorphine [byoo-pre-NOR-feen] is classified as a partial agonist, acting at the μ receptor. It acts like morphine in naïve patients, but it can also precipitate withdrawal in users of morphine or other full opioid agonists. Pentazocine Pentazocine [pen-TAZ-oh-seen] acts as an agonist on κ receptors and is a weak antagonist at μ and δ receptors. Pentazocine promotes analgesia by activating receptors in the spinal cord, and it is used to relieve moderate pain. It may be administered either orally or parenterally. Nalbuphine and butorphanol Nalbuphine [NAL-byoo-feen] and butorphanol [byoo-TOR-fa-nole] are mixed opioid agonist–antagonists.

Other analgesic Tramadol Tramadol [TRA-ma-dole] is a centrally acting analgesic that binds to the μ opioid receptor. The drug undergoes extensive metabolism via CYP450 2D6, leading to an active metabolite with a much higher affinity for the μ receptor than the parent compound. In addition, it weakly inhibits reuptake of norepinephrine and serotonin. It is used to manage moderate to moderately severe pain. Its respiratory depressant activity is less than that of morphine. Naloxone can only partially reverse the analgesia produced by tramadol or its active metabolite. As with other agents that bind the μ opioid receptor, tramadol has been associated with misuse and abuse.

Opoids Antagonists The opioid antagonists bind with high affinity to opioid receptors, but fail to activate the receptor-mediated response. Administration of opioid antagonists produces no profound effects in normal individuals. However, in patients dependent on opioids, antagonists rapidly reverse the effect of agonists, such as morphine or any full μ agonist, and precipitate the symptoms of opioid withdrawal.

A. Naloxone Naloxone [nal-OX-own] is used to reverse the coma and respiratory depression of opioid overdose. It rapidly displaces all receptor-bound opioid molecules and, therefore, is able to reverse the effect of a morphine overdose. Within 30 seconds of IV injection of naloxone, the respiratory depression and coma characteristic of high doses of morphine are reversed, causing the patient to be revived and alert. Naloxone has a half-life of 30 to 81 minutes; therefore, a patient who has been treated and recovered may lapse back into respiratory depression. Naloxone is a competitive antagonist at μ, κ, and δ receptors, with a 10-fold higher affinity for μ than for κ receptors. This may explain why naloxone readily reverses respiratory depression with only minimal reversal of the analgesia that results from agonist stimulation of κ receptors in the spinal cord. There is little to no clinical effect seen with oral naloxone, upon IV administration, opioid antagonism occurs, and the patient experiences withdrawal. This is why naloxone has been combined with oral opioids to deter IV drug abuse.

B. Naltrexone Naltrexone [nal-TREX-own] has actions similar to those of naloxone. It has a longer duration of action than naloxone, a single oral dose of naltrexone blocks the effect of injected heroin for up to 24 hours. Naltrexone in combination with clonidine (and, sometimes, with buprenorphine) is used for rapid opioid detoxification. Although it may also be beneficial in treating chronic alcoholism by an unknown mechanism, benzodiazepines and clonidine are preferred. Naltrexone can lead to hepatotoxicity.