12/17/18 Analgesics Opioids" Pharmacology Dr. Hiwa K. Saaed PhD Pharmacology & Toxicology College of Pharmacy, University of Sulaimani 2018-2019 1 Analgesic Analgesic an agent that selectively relieves pain by acting in the CNS or on peripheral pain mechanisms, without significantly altering the consciousness Pain is an unpleasant sensation that can be either: Acute or Chronic Consequence of complex neurochemical processes in the peripheral and CNS. Subjective: the clinician must rely on the patient s perception and description of pain. Alleviation of pain depend on its type Nociceptive pain: Headache, arthritic pain Rx NSAIDs Neuropathic pain Rx TCA Amitriptyline or SSRI Fluoxetine or SNRI Severe or chronic malignant pain Rx Opiods are DOC 2 1
Definitions: Ancient Egypt papyrus records reported the use of opium for pain Relief Definitions: MORPHEUS- GREAK GOD OF DREAMS Opium mixture of alkaloids from the poppy seed. Opiates naturally occurring alkaloids such as morphine or codeine obtained from the juice of the opium poppy. Opioid broad term to describe all natural or synthetic compounds that work at the opioid receptors and produce morphine-like effects. Opioids act by binding to specific opioid receptors in the CNS to produce the action of endogenous peptide neurotransmitters: endorphin, enkephalins & dynorphins 3 Opioid Classifications Chemistry Natural Semisynthetic Synthetic OPIOID RECEPTOR Mu(μ) Kappa(κ) Delta (δ) INTRINSIC ACTIVITY agonist, partial/weak agonist, antagonist Mixed agonist/antagonist 4 2
INTRINSIC ACTIVITY Strong Alfentanil Fentanyl Heroin Meperidine Methadone Morphine Oxycodone Remifentanil Sufentanil Moderate/low Codeine Propoxyphene Tramadol Mixed agonist/antagonist & partial agonist Buprenorphine Butorphanol Nalbuphine Pentazocine Antagonists Nalmefene Naloxone naltrexone Endogenous opioid receptors Mu (μ) Analgesia (supraspinal) Miosis Respiratory depression Euphoria Physical dependence Decrease GIT motility Delta (δ) analgesia (spinal & supraspinal) release of growth hormone Affective behavior Present in limbic system Kappa (κ) Spinal analgesia Sedation miosis Sigma less specific bind with non opioid agent e.g hallucinogen Dysphoria Hallucination (both visual & auditory) Respiratory and vasomotor stimulation mydriasis 6 3
Opioid receptors Opioids interact with receptors on the: membranes of certain cells in the CNS, nerve terminals in the periphery cells of the GIT and the anatomic regions urinary bladder. Analgesic properties are mediated: mainly via μ receptors: that modulate responses to thermal, mechanical, and chemical nociception. and κ receptors of the dorsal horn of the spinal cord by modulating the response to chemical and thermal nociception. Enkephalins interact more selectively with the δ receptors in the periphery. 7 Mechanism of Action All are G-protein coupled receptors and inhibit adenylate cyclase. They inhibit neuronal activity by: postsynaptic hyperpolarization (increasing K+ efflux and decreases the response to excitatory NT) reducing presynaptic Ca ++ influx; decreases release of excitatory NT; glutamate Receptor distribution High densities of opioid receptors on peripheral nerve fibers, they inhibit Ca +2 dependent release of excitatory, pro-inflammatory substances (substance P) immune cells: undetermined CNS; five general areas of the CNS: 8 4
Receptor distribution CNS; five general areas of the CNS: 1. Brainstem: respiration, cough, nausea & vomiting, BP, pupillary diameter and stomach secretion. 2. Medial thalamus: mediating poorly localized deep pain 3. Spinal cord: in the substantia gelatinosa are involved in the receipt & integration on sensory input leading to the attenuation of painful afferent stimuli. 4. Hypothalamus: neuroendocrine secretion. 5. Limbic system: the greatest concentration in the amygdale, a major role in emotional behavior & response and little analgesic effect. 9 Opioid Agonists The strongest naturally occurring analgesic drugs are found in opium from the poppy flower, morphine and less potent codeine. These drugs show: a high affinity for the μ receptor and less affinity for the κ and δ receptors. Mechanism of Action: interaction with central & peripheral opioid receptors, results in hyperpolarization, inhibition of nerve firing and presynaptic inhibition of transmitter release. Morphine also acts at κ receptors in lamina I and II of the dorsal horn of the spinal cord. It decreases the release of substance P, which modulates pain perception in the spinal cord. Morphine also appears to inhibit the release of many excitatory transmitters from nerve terminals carrying nociceptive (painful) stimuli. 5
Morphine-Pharmacological Actions Analgesia: Opioids cause pain relief by both q raising the pain threshold at the spinal cord level q altering the central perception of pain; awareness of pain remains but it loses its unpleasant character Euphoria: Opioids produce a sense of contentment and well being, this may be related to stimulation of the ventral tegmental tract. Respiration: respiratory depression by decreasing the sensitivity of central respiratory neurons to CO 2. Occurs at therapeutic doses and as dose increases respiratory arrest will occur. Suppression of cough reflex: Antitussive properties do not correlate with analgesic or respiratory depression effects; this appears mediated via a different receptor complex. 11 Morphine-Pharmacological Actions Miosis: Results from stimulation of μ and κ receptors located in the Edinger-Westphal nucleus of CN III, resistant to tolerance, all morphine abusers demonstrate pinpoint pupils. NB: This is important diagnostically, because many other causes of coma and respiratory depression produce dilation of the pupil. Emesis: Opioids directly stimulate the chemoreceptor trigger zone in the area postrema that causes vomiting GI tract: Opioids relieve diarrhea by decreasing gut motility and increasing the tone of intestinal smooth muscle & of the anal sphincter. Constipation is also resistant to tolerance. Biliary spasm is exacerbated by increasing biliary tone with sphincter of Oddi spasm. Cardiovascular: At large doses morphine produces hypotension & bradycardia. Because of respiratory depression and carbon dioxide retention, cerebral vessels dilate and increase cerebrospinal fluid pressure. Therefore, morphine is usually contraindicated in individuals with head trauma or severe brain injury. 12 6
Morphine-Pharmacological Actions Histamine release: Morphine causes mast cell degranulation, the release of histamine causing urticaria, itching, diaphoresis and vasodilation. In asthmatics it may precipitate bronchospasm Hormonal Actions: Inhibits the release of GnRH, CRH Deceases the release of LH, FSH, ACTH and β-endorphin Decrease levels of Testosterone and cortisol Increase Prolactin and GH release via suppression of dopamine levels centrally Increase ADH release Labor: Morphine may prolong the second stage of labor by transiently decreasing the strength, duration, and frequency of uterine contractions. 13 Morphine-Therapeutic Uses- Analgesia: Few drugs are as effective as morphine for the relief of pain Treatment of Diarrhea: Loperamide, Diphenoxylate Anti-tussive: codeine and dextromethorphanare congeners with greater antitussive effects Acute Pulmonary Edema: IV morphine dramatically relieves the dyspnea associated with pulmonary edema due to LV failure 14 7
Morphine- Pharmacokinetics Administration: Morphine is poorly absorbed orally; codeine is a much more effective oral analgesic. Both undergo extensive first pass metabolism in the liver. Inhalation is an effective route but has found favor only with non-medicinal administration Implantable morphine pumps are also now use for chronic pain Distribution: Morphine readily enters all body tissues except the brain; morphine is the least lipid soluble of the opiates (fentanyl, methadone and heroin all enter the CNS much more quickly) 15 Metabolism: Morphine- Pharmacokinetics - Conjugated in the liver, morphine 6-glucuronide is a much more potent analgesic; however morphine-3-glucuronide is less analgesic. Both are excreted in the urine with small amounts excreted in the bile Hepatic & renal dysfunction both prolong the normal 4-6 hour duration of action when administered systemically to morphine-naive individuals but considerably longer when injected epidurally, because its low lipophilicity prevents redistribution from the epidural space. 16 8
Morphine- Pharmacokinetics - A patient's age can influence the response to morphine: Elderly patients are more sensitive to the analgesic effects of the drug, possibly due to: decreased metabolism or other factors, such as decreased lean body mass, renal function, etc. They should be treated with lower doses. Neonates should not receive morphine because of their low conjugating capacity. 17 Morphine- Adverse Effects Severe respiratory depression (μ, δ and κ receptors) Constipation (variable, μ and κ receptors) Nausea and vomiting Pupillary constriction (μ/κ receptors) Allergy enhanced hypotensive effects Elevation of intracranial pressure particularly head injury Enhance cerebral and spinal ischemia In BPH, morphine cause acute urinary retention. 18 9
Morphine- Adverse Effects - Patients with adrenal insufficiency or myxedema may experience extended and increased effects from the opioids. Morphine should be used with cautiously in patients with bronchial asthma or renal, liver failure. Rapid development of tolerance, Physical dependence and abstinence syndrome Drug interactions: The depressant actions of morphine are enhanced by phenothiazines, MAOIs, and TCAs. The analgesia inexplicably enhanced by Low doses of amphetamine and hydroxyzine. 19 Tolerance & Physical Dependence- Repeated use produces tolerance to the effects of respiratory depression, analgesia, euphoria and sedation. Tolerance does not develop to miosis and constipation Physical & psychological dependence readily occurs. Withdrawal induces a syndrome associated with autonomic, motor and psychological responses that are incapacitating, rarely are these life threatening Detoxification of heroin- or morphine-dependent individuals is usually accomplished through the oral administration of methadone, buprenorphine, or clonidine. 20 10
Opioid withdrawal syndrome 21 Meperidine Pethidine (μ, κ) A synthetic opioid structurally unrelated to morphine Mechanism: It binds to μ receptors with some binding at κ receptors Actions: respiratory depression similar to morphine, but less urine retention no significant CV effect when given orally. IV administration produces a decrease in PVR resulting in increased peripheral blood flow & HR. pupillary dilation via an atropine like effect. 22 11
Therapeutic uses: Severe acute pain Lacks antitussive activity No anti diarrhea; Meperidine Obstetrics; Produces less smooth muscle contraction/ spasm than morphine Pharmacokinetics: Well absorbed form the GI tract; it is most often given IM Shorter duration of action than morphine (2-4 hours) Demethylated to normeperidine in the liver and excreted in the urine NB. Because of shorter action and different route of metabolism, meperidine is preferred over morphine during labor 23 Meperidine-Adverse effects: With large repeated doses normeperidine (demethylated meperidine) accumulates causing anxiety, muscle tremors and convulsions Causes pupillary dilation (vs. miosis with morphine) in large doses Hyperactive reflexes Severe hypotension when admin. postop. + neuroleptics: enhanced depression + MAOI: severe reactions convulsion & hyperthermia Cross-tolerance with other opioids 24 12
Methadone (μ) This is a synthetic orally effective opioid that is equipotent to morphine but induces less euphoria has a longer duration of action Mechanism of action: Binds to the μ receptor. Actions: An equipotent analgesic to morphine Causes miosis, respiratory depression, biliary spasm and constipation just like morphine. 25 Methadone Therapeutic uses: Used for controlled withdrawal from heroin & morphine Self addictive but the withdrawal syndrome is somewhat milder but more protracted than with other opioids Pharmacokinetics: Readily absorbed orally, t 1/2 24hrs Highly protein bound so remains in tissues for a prolonged period. Transformed in the liver and excreted by the urine as mostly inactive metabolites Adverse effects: Similar to morphine particularly the risk of addiction 26 13
Fentanyl Chemically related to meperidine but miosis has 100 times the analgesic potency of morphine; used in anesthesia and as analgesia postoperatively & during labor Highly lipophilic: elimination half-life is longer than morphine s as redistribution occurs Rapid onset of action and a short duration (15-30 minutes) Can be used IV, epidurally or intrathecally. Transmucosal and transdermal preparations are available Metabolized to an inactive metabolite by the cytochrome P4503A4 system. Drug metabolites are eliminated through the urine. 27 Fentanyl Like morphine fentanyl causes miosis (vs. mydriasis) Particular risk of the transmucosal or transdermal routes is respiratory depression; these delivery routes create a reservoir of drug in the skin or mucosa. Hence, the onset is delayed 12 hours, and the offset is prolonged Fentanyl is often used during cardiac surgery because of its negligible effects on myocardial contractility. Muscular rigidity, primarily of the abdomen and chest wall, is often observed with fentanyl use in anesthesia. Adverse effects of fentanyl are similar to those of other µ- receptor agonists. 28 14
Fentanyl Because of life-threatening hypoventilation, the fentanyl patch is contraindicated in the management of acute and postoperative pain or pain that can be ameliorated with other analgesics. Fentanyl derivative: Sufentanil, Alfentanil & Remifentanil are related to fentanyl they differ in their potency and metabolic disposition. Only Sufentanil is even more potent than fentanyl others are less potent 29 Heroin Heroin is produced by the diacetylation of morphine which results in a three fold increase in its potency Acetylation allows it to cross the BBB much more rapidly yielding a more pronounced euphoria May be used IV or smoked, both allow for rapid distribution, heroin is metabolized to morphine No medical indication for its use in the clinic. 30 15
oxycodone is a semisynthetic derivative of morphine. It is orally active and is sometimes formulated with aspirin or acetaminophen. It is used to treat moderate to severe pain and has many properties in common with morphine. Oxycodone is metabolized to products with lower analgesic activity. Excretion is via the kidney. Abuse of the sustained-release preparation (ingestion of crushed tablets) has been implicated in many deaths. It is important that the higher-dosage forms of the latter preparation be used only by patients who are tolerant to opioids. 31 Moderate/Weak Agonists Codeine: Converte to morphine thus: Much less analgesic than morphine Less euphoria and has much lower abuse potential and rarely produces physical dependence An effective oral analgesic Does possess significant anti-tussive effects at sub-analgesic doses Often formulated with either acetaminophen, aspirin of ibuprofen; care but be exerted when these are used with over the counter analgesic to avoid overdose with the non-opioid agent A synthetic congener of codeine dextromethorphan lacks analgesic properties is an effective anti-tussive available without prescription 32 16
Moderate/Weak Agonists Propoxyphene Derivative of methadone, dextro isomer is analgesic, levo isomer is antitussive Used for mild to moderate pain; its opioid dose equipotency is about half of codeine (require twice dose) Often formulated with another over-the-counter analgesic; combination has greater effect than either drug alone Toxic doses may produce cardio and pulmonary toxicity particularly when taken in combination with alcohol and/or sedatives in addition to CNS depression Opioid antagonists can reverse the pulmonary and CNS effects but not the cardiotoxicity 33 Mixed Agonists-Antagonists & Partial Agonists Pentazocine, Buprenorphine, Butorphanol, Nalbuphine Drugs that stimulate one receptor but block another. Effects of these drugs depend on previous exposure to opioids: Naïve patients drugs act as agonists; produce pain relief Opioid dependent patients drugs show blocking affects; withdrawal syndrome Pentazocine acts as an agonist on k receptors and is a weak antagonist at µ and delta 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. Pentazocine produces less euphoria compared to morphine. 34 17
Pentazocine In higher doses, the drug causes respiratory depression and decreases the activity of the gastrointestinal tract. High doses increase blood pressure and can cause hallucinations, nightmares, dysphoria, tachycardia, and dizziness. The latter properties have led to its decreased use. In angina, pentazocine increases the mean aortic pressure and pulmonary arterial pressure and, thus, increases the work of the heart. The drug decreases renal plasma flow. Despite its antagonist action, pentazocine does not antagonize the respiratory depression of morphine, but it can precipitate a withdrawal syndrome in a morphine abuser. Tolerance and dependence develop on repeated use. 35 Mixed Agonists-Antagonists & Partial Agonists Buprenorphine A partial agonist at μ receptors producing morphine-like effects in naïve users but precipitating withdrawal in morphine dependents Metabolized in the liver and excreted in the urine and bile May be taken sublingually or parenteral and possess a long duration of action Adverse effects respiratory depression not reversible by naloxone, hypotension and nausea Main use is in opioid detoxification as its withdrawal syndrome appears less severe and of shorter duration than methadone Available outside of the specialized clinic allowed to dispense methadone for opiate withdrawal. 36 18
Antagonists Bind with high affinity to the μ, κ & δ receptors but fail to activate the receptor In normal individuals, these agents produce no effect but in those with opiates present, they induce an acute withdrawal syndrome Naloxone Reverses the coma and respiratory depression associated with opioid overdose IV administration produces a reversal of respiratory depression within ~30 seconds Binding affinity is 10X greater at the μ receptor than κ Relatively short T 1/2 (60-100 minutes) so reversal will often abate requiring repeat administration 37 Naltrexone (hepatotoxic) Antagonists Similar actions as naloxone but an oral agent with a much longer duration of action Single dose able to antagonize the effects of heroin for up to 48 hours Nalmefene is a parenteral opioid antagonist with actions similar to that of naloxone and naltrexone. It can be administered IV, intramuscularly, or subcutaneously. Its half-life of 8 to10 hours is significantly longer than that of naloxone and several opioid agonists. 38 19