Opioids Lecture PDF

 Opioid-any substance whether endogenous or synthetic that produces morphine like effects that are blocked by antagonists eg naloxone  Opiate-compounds like morphine found in the opium poppy plant  Narcotic analgesic-old term for opiods  Narcotic –anything that can induce sleep  Morp...

 Opioid-any substance whether endogenous or synthetic that produces morphine like effects that are blocked by antagonists eg naloxone  Opiate-compounds like morphine found in the opium poppy plant  Narcotic analgesic-old term for opiods  Narcotic –anything that can induce sleep  Morphine, the prototypical opioid agonist, has long been known to relieve severe pain.  The opium poppy is the source of crude opium from which Serturner in 1803 isolated morphine, the pure alkaloid and named it after Morpheus, the Greek god of dreams . It remains the standard against which all drugs that have strong analgesic action are compared.  These drugs are collectively known as opioid analgesics  They include:  natural alkaloids  semi synthetic alkaloid derivatives  synthetic surrogates,  opioid-like drugs whose actions are blocked by the nonselective antagonist naloxone  Endogenous peptides that interact with the several subtypes of opioid receptors.  Morphine is a phenanthrene derivative  Opioid activity is possible through free hydroxyl groups on its benzene ring  Variants of morphine has been produced by substitution of the hydroxyl groups eg diamorphine, codeine and oxycodone  Substitution on the nitrogen atom has produced antagonists eg naloxone  Phenylpiperidine series 1. meperidine(pethidine) 2. Fentanyl,alfetanyl and sulfentanil---are shorter acting but more potent, 3. Remifentanyl is an analogue of fentanyl  Methadone series 1. METHADONE---------has no structural resemblance to morphine  Benzomorphan series 1. Pentazocine 2. cyclazocine  Thebaine derivatives 1. Buprenorphine-very potent, partial agonist 2. Etorphine-very potent, full agonists, used in veterinary practice DRUG POTENCY (MORPHINE=1) codeine 0.1 dihydrocodeine 0.1 Tramadol 0.2 pethidine 0.1 morphine 1 diamorphine 2.5 hydromorphone 7 methadone 2-10 fentanyl 150  Source  Opium, the source of morphine, is obtained from the poppy, Papaver somniferum and P album.  After incision, the poppy seed pod exudes a white substance that turns into a brown gum that is crude opium.  Opium contains many alkaloids, the principle one being morphine, which is present in a concentration of about 10%.  Codeine is synthesized commercially from morphine.  Opioid drugs include  Full agonists  Partial agonists,  Antagonists Morphine is a full agonist at the u (mu) opioid receptor, the major analgesic opioid receptor  Codeine functions as a partial (or "weak") u- receptor agonist  Simple substitution of an allyl group on the nitrogen of the full agonist morphine plus addition of a single hydroxyl group results in naloxone, a strong u-receptor antagonist. . Some opioids, eg, nalbuphine, are capable of producing an agonist (or partial agonist) effect at one opioid receptor subtype and an antagonist effect at another.  Not only can the activating properties of opioid analgesics be manipulated by pharmaceutical chemistry, certain opioid analgesics are modified in the liver, resulting in compounds with greater analgesic action o Opioid alkaloids (eg, morphine) produce analgesia through actions at regions in the central nervous system (CNS) that contain peptides with opioid-like pharmacologic properties. o The general term currently used for these endogenous substances is endogenous opioid peptides.  Three families of endogenous opioid peptides have been described in detail:  the endorphins, the pentapeptides methionine-enkephalin (met-enkephalin)  leucine-enkephalin (leu-enkephalin),  dynorphins . The three families of opioid receptors have overlapping affinities for these endogenous peptides  ABSORPTION Most opioid analgesics are well absorbed when given by subcutaneous, intramuscular, and oral routes. However, because of the first-pass effect, the oral dose of the opioid (eg, morphine) may need to be much higher than the parenteral dose to elicit a therapeutic effect. Considerable interpatient variability exists in first-pass opioid metabolism, making prediction of an effective oral dose difficult . Certain analgesics such as codeine and oxycodone are effective orally because they have reduced first-pass metabolism . Nasal insufflation of certain opioids can result in rapid therapeutic blood levels by avoiding first-pass metabolism.  Other routes of opioid administration include oral mucosa via lozenges, and transdermal via transdermal patches. The latter can provide delivery of potent analgesics over days.  The uptake of opioids by various organs and tissues is a function of both physiologic and chemical factors.  all opioids bind to plasma proteins with varying affinity,  The drugs rapidly leave the blood compartment and localize in highest concentrations in tissues that are highly perfused such as the brain, lungs, liver, kidneys, and spleen.  Drug concentrations in skeletal muscle may be much lower, but this tissue serves as the main reservoir because of its greater bulk  Blood flow to fatty tissue is much lower than to the highly perfused tissues,  accumulation can be very important, particularly after frequent high-dose administration or continuous infusion of highly lipophilic opioids that are slowly metabolized, eg, fentanyl.  The opioids are converted in large part to polar metabolites (mostly glucuronides), which are then readily excreted by the kidneys.  For example, morphine, which contains free hydroxyl groups, is primarily conjugated to morphine-3-glucuronide (M3G), a compound with neuroexcitatory properties.  The neuroexcitatory effects of M3G do not appear to be mediated by u receptors but rather by the GABA/glycinergic system  Incontrast, approximately 10% of morphine is metabolized to morphine-6-glucuronide (M6G), an active metabolite with analgesic potency four to six times that of its parent compound.  However, these relatively polar metabolites have limited ability to cross the blood-brain barrier and probably do not contribute significantly to the usual CNS effects of morphine  Accumulation of these metabolites may produce unexpected adverse effects in patients with renal failure or when exceptionally large doses of morphine are administered or high doses are administered over long periods  Thiscan result in M3G-induced CNS excitation (seizures) or enhanced and prolonged opioid action produced by M6G.  CNS uptake of M3G and, to a lesser extent, M6G can be enhanced by coadministration with probenecid or with drugs that inhibit the P-glycoprotein drug transporter.  Like morphine, hydromorphone is metabolized by conjugation, yielding hydromorphone-3-glucuronide (H3G), which has CNS excitatory properties. Hydromorphone has not been shown to form significant amounts of a 6-glucuronide metabolite The effects of these active metabolites should be considered before the administration of morphine or hydromorphone, especially when given at high doses  Hepatic oxidative metabolism is the primary route of degradation of the phenylpiperidine opioids (meperidine, fentanyl, alfentanil, sufentanil)  only small quantities of the parent compound unchanged for excretion.  However, accumulation of a demethylated metabolite of meperidine, normeperidine, may occur in patients with decreased renal function and in those receiving multiple high doses of the drug.  In high concentrations, normeperidine may cause seizures.  In contrast, no active metabolites of fentanyl have been reported.  The P450 isozyme CYP3A4 metabolizes fentanyl by N-dealkylation in the liver. CYP3A4 is also present in the mucosa of the small intestine and contributes to the first- pass metabolism of fentanyl when it is taken orally.  Codeine, oxycodone, and hydrocodone undergo metabolism in the liver by P450 isozyme CYP2D6, resulting in the production of metabolites of greater potency.  For example, codeine is demethylated to morphine.  Genetic polymorphism of CYP2D6 has been documented and linked to the variation in analgesic response seen among patients  Nevertheless, the metabolites of oxycodone and hydrocodone may be of minor consequence because the parent compounds are currently believed to be directly responsible for the majority of their analgesic actions.  In the case of codeine, conversion to morphine may be of greater importance because codeine itself has relatively low affinity for opioid receptors.  Polar metabolites, including glucuronide conjugates of opioid analgesics, are excreted mainly in the urine.  Small amounts of unchanged drug may also be found in the urine.  In addition, glucuronide conjugates are found in the bile, but enterohepatic circulation represents only a small portion of the excretory process.. MECHANISM OF ACTION Opioid agonists produce analgesia by binding to specific G protein-coupled receptors that are located in brain and spinal cord regions involved in the transmission and modulation of pain.  Three major classes of opioid receptors  Mu  delta,(d)  kappa(k)  Each of the three major receptors has now been cloned  All are members of the G protein-coupled family of receptors and show significant amino acid sequence homologies . Multiple receptor subtypes have been proposed based on pharmacologic criteria, including  u1, u2; d1, d2;  k1, k2, and k3.  An opioid drug may function with different potencies as an agonist, partial agonist, or antagonist at more than one receptor class or subtype,  These agents are capable of diverse pharmacologic effects..  The majority of currently available opioid analgesics act primarily at the u opioid receptor.  Analgesia, as well as the euphoriant, respiratory depressant, and physical dependence properties of morphine result principally from actions at u receptors.  In fact, the u receptor was originally defined using the relative potencies for clinical analgesia of a series of opioid alkaloids.  However, opioid analgesic effects are complex and include interaction with d and k receptors.  The development of d-receptor-selective agonists could be clinically useful if their side-effect profiles (respiratory depression, risk of dependence) were more favorable than those found with current u-receptor agonists, such as morphine.  Although morphine does act at k and d receptor sites, it is unclear to what extent this contributes to its analgesic action.  The endogenous opioid peptides differ from most of the alkaloids in their affinity for the d and k  At the molecular level, opioid receptors form a family of proteins that physically couple to G proteins  This interaction affect ion channel gating, modulate intracellular Ca2+ disposition, and alter protein phosphorylation  Inan effort to develop opioid analgesics with a reduced incidence of respiratory depression or propensity for addiction and dependence,  compounds that show preference for k opioid receptors have been developed.  Butorphanol and nalbuphine have shown some clinical success as analgesics, but they can cause dysphoric reactions and have limited potency.  Opioid receptor binding sites have been localized  All three major receptors are present in high concentrations in the dorsal horn of the spinal cord.  Receptors are present both on spinal cord pain transmission neurons and on the primary afferents that relay the pain message to them  Opioid agonists inhibit the release of excitatory transmitters from these primary afferents  They directly inhibit the dorsal horn pain transmission neuron . Thus, opioids exert a powerful analgesic effect directly on the spinal cord.  This spinal action has been exploited clinically by direct application of opioid agonists to the spinal cord, which provides a regional analgesic effect while reducing the unwanted respiratory depression, nausea and vomiting, and sedation that may occur from the supraspinal actions of systemically administered opioids.  opioids are given systemically and so act simultaneously at multiple sites . These include  the ascending pathways of pain transmission beginning with specialized peripheral sensory terminals that transduce painful stimuli  Descending pathway  At these sites as at others, opioids directly inhibit neurons;  yet this action results in the activation of descending inhibitory neurons that send processes to the spinal cord and inhibit pain transmission neurons . This activation has been shown to result from the inhibition of inhibitory neurons in several locations  Taken together, interactions at these sites increase the overall analgesic effect of opioid agonists.  When pain-relieving opioid drugs are given systemically, they presumably act upon brain circuits normally regulated by endogenous opioid peptides.  Part of the pain-relieving action of exogenous opioids involves the release of endogenous opioid peptides.  An exogenous opioid agonist (eg, morphine) may act primarily and directly at the u receptor, but this action may evoke the release of endogenous opioids  that additionally act at d and k receptors.  Thus, even a receptor-selective ligand can initiate a complex sequence of events involving multiple synapses, transmitters, and receptor types.  repeated therapeutic doses of morphine or its surrogates, there is a gradual loss in effectiveness, ie, tolerance . To reproduce the original response, a larger dose must be administered.  Along with tolerance, physical dependence develops  Physical dependence is defined as a characteristic withdrawal or abstinence syndrome when a drug is stopped or an antagonist is administered  Inaddition to the development of tolerance, persistent administration of opioid analgesics has been observed to increase the sensation of pain leading to a state of hyperalgesia.  This phenomenon has been observed with several opioid analgesics, including morphine, fentanyl, and remifentanyl  The actions described below for morphine, the prototypic opioid agonist, can also be observed with other opioid agonists, partial agonists, and those with mixed receptor effects.  The principal effects of opioid analgesics with affinity for u receptors are on the CNS; the more important ones include  analgesia,  euphoria,  sedation,  respiratory depression. . Pain consists of both sensory and affective (emotional) components. Opioid analgesics are unique in that they can reduce both aspects of the pain experience, especially the affective aspect.  Typically, patients or intravenous drug users who receive intravenous morphine experience a pleasant floating sensation with lessened anxiety and distress.  However, dysphoria, an unpleasant state characterized by restlessness and malaise, may sometimes occur.  Drowsiness and clouding of mentation are common concomitants of opioid action.  There is little or no amnesia.  Sleep is induced by opioids more frequently in the elderly than in young, healthy individuals. . Marked sedation occurs more frequently with compounds closely related to the phenanthrene derivatives  and less frequently with the synthetic agents such as meperidine and fentanyl.  In standard analgesic doses, morphine (a phenanthrene) disrupts normal REM and non-REM sleep patterns.   All of the opioid analgesics can produce significant respiratory depression by inhibiting brainstem respiratory mechanisms . Alveolar PCO2 may increase, but the most reliable indicator of this depression is a depressed response to a carbon dioxide challenge  The respiratory depression is dose-related and is influenced significantly by the degree of sensory input occurring at the time.  For example, it is possible to partially overcome opioid-induced respiratory depression by stimulation of various sorts . When strongly painful stimuli that have prevented the depressant action of a large dose of an opioid are relieved, respiratory depression may suddenly become marked.  A small to moderate decrease in respiratory function, as measured by PaCO2 elevation, may be well tolerated in the patient without prior respiratory impairment.  However, in individuals with increased intracranial pressure, asthma, chronic obstructive pulmonary disease, or cor pulmonale, this decrease in respiratory function may not be tolerated  Suppression of the cough reflex is a well- recognized action of opioids . Codeine in particular has been used to advantage in persons suffering from pathologic cough and in patients in whom it is necessary to maintain ventilation via an endotracheal tube  cough suppression by opioids may allow accumulation of secretions and thus lead to airway obstruction and atelectasis.  Constriction of the pupils is seen with virtually all opioid agonists.  Miosis is a pharmacologic action to which little or no tolerance develops  it is valuable in the diagnosis of opioid overdose.  Even in highly tolerant addicts, miosis is seen.  This action, which can be blocked by opioid antagonists, is mediated by parasympathetic pathways, which, in turn, can be blocked by atropine.  An intensification of tone in the large trunk muscles has been noted with a number of opioids. It was originally believed that truncal rigidity involved a spinal cord action of these drugs , This is a result from an action at supraspinal levels. Truncal rigidity reduces thoracic compliance and thus interferes with ventilation. The effect is most apparent when high doses of the highly lipid-soluble opioids (eg, fentanyl, sufentanil, alfentanil, remifentanil) are rapidly administered intravenously. Truncal rigidity may be overcome by administration of an opioid antagonist, This will also antagonize the analgesic action of the opioid. Preventing truncal rigidity while preserving analgesia requires the concomitant use of neuromuscular blocking agents.  The opioid analgesics can activate the brainstem chemoreceptor trigger zone to produce nausea and vomiting  There may also be a vestibular component in this effect because ambulation seems to increase the incidence of nausea and vomiting.  Homeostatic regulation of body temperature is mediated in part by the action of endogenous opioid peptides in the brain.  This has been supported by experiments demonstrating that u opioid receptor agonists such as morphine administered to the anterior hypothalamus produces hyperthermia, whereas administration of k agonists induce hypothermia.  Cardiovascular system  Most opioids have no significant direct effects on the heart and, other than bradycardia, no major effects on cardiac rhythm . Meperidine is an exception to this generalization because its antimuscarinic action can result in tachycardia . Blood pressure is usually well maintained in subjects receiving opioids unless the cardiovascular system is stressed, in which case hypotension may occur.   This hypotensive effect is probably due to  peripheral arterial and venous dilation, which has been attributed to a number of mechanisms including  central depression of vasomotor-stabilizing mechanisms  release of histamine.  No consistent effect on cardiac output is seen, and the electrocardiogram is not significantly affected  caution should be exercised in patients with decreased blood volume, because the above mechanisms make these patients susceptible to hypotension  . Opioid analgesics affect cerebral circulation minimally except when PCO2 rises as a consequence of respiratory depression . Increased PCO2 leads to cerebral vasodilation associated with a decrease in cerebral vascular resistance, an increase in cerebral blood flow, and an increase in intracranial pressure.  Constipation has long been recognized as an effect of opioids, an effect that does not diminish with continued use  Tolerance does not develop to opioid-induced constipation  Opioid receptors exist in high density in the gastrointestinal tract, and the constipating effects of the opioids are mediated through an action on the enteric nervous system as well as the CNS . In the stomach, motility (rhythmic contraction and relaxation) may decrease but tone (persistent contraction) may increase  gastric secretion of hydrochloric acid is decreased.  Small intestine resting tone is increased, with periodic spasms, but the amplitude of nonpropulsive contractions is markedly decreased . In the large intestine, propulsive peristaltic waves are diminished and tone is increased;  This delays passage of the fecal mass and allows increased absorption of water, which leads to constipation.  The large bowel actions are the basis for the use of opioids in the management of diarrhea.  The opioids contract biliary smooth muscle, which can result in biliary colic  The sphincter of Oddi may constrict, resulting in reflux of biliary and pancreatic secretions and elevated plasma amylase and lipase levels.  Renal function is depressed by opioids.  It is believed that in humans this is chiefly due to decreased renal plasma flow.  In addition, u opioids have been found to have an antidiuretic effect in humans.  Mechanisms may involve both the CNS and peripheral sites.  Opioids also enhance renal tubular sodium reabsorption.   Therole of opioid-induced changes in antidiuretic hormone (ADH) release is controversial.  Ureteral and bladder tone are increased by therapeutic doses of the opioid analgesics. Increased sphincter tone may precipitate urinary retention, especially in postoperative patients. Occasionally, ureteral colic caused by a renal calculus is made worse by opioid- induced increase in ureteral tone.  The opioid analgesics may prolong labor. The mechanism for this action is unclear  , Both peripheral and central actions of the opioids can reduce uterine tone.  Opioid analgesics stimulate the release of ADH, prolactin, and somatotropin but inhibit the release of luteinizing hormone.  These effects suggest that endogenous opioid peptides, through effects in the hypothalamus, regulate these systems  Therapeutic doses of the opioid analgesics produce flushing and warming of the skin accompanied sometimes by sweating and itching;  CNS effects and peripheral histamine release may be responsible for these reactions . Opioid-induced pruritus and occasionally urticaria appear more frequently when opioid analgesics are administered parenterally . In addition, when opioids such as morphine are administered to the neuraxis by the spinal or epidural route, their usefulness may be limited by intense pruritus over the lips and torso.  The opioids modulate the immune system by  Effects ON  on lymphocyte proliferation,  antibody production,  and chemotaxis.  Natural killer cell cytolytic activity  and lymphocyte proliferative responses to mitogens are usually inhibited by opioids  Lecture 2 opiods. ANALGESIA Severe, constant pain is usually relieved with opioid analgesics with high intrinsic activity sharp, intermittent pain does not appear to be as effectively controlled. The pain associated with cancer and other terminal is managed by opioids  Research has demonstrated that fixed- interval administration of opioid medication (ie, a regular dose at a scheduled time) is more effective in achieving pain relief than dosing on demand.  New dosage forms of opioids that allow slower release of the drug are now available, eg, sustained-release forms of morphine (MSContin) and oxycodone (OxyContin).  Their advantage is a longer and more stable level of analgesia.  Administration of strong opioids by nasal insufflations has been shown to be efficacious, and nasal preparations are now available In addition, stimulant drugs such as the amphetamines have been shown to enhance the analgesic actions of the opioids and thus may be very useful adjuncts in the patient with chronic pain.  Opioid analgesics are often used during obstetric labor. Because opioids cross the placental barrier and reach the fetus,care must be taken to minimize neonatal depression.  Neonatal respiratory depression is reversed by immediate injection of the antagonist naloxone The phenylpiperidine drugs (eg, meperidine) appear to produce less depression, particularly respiratory depression, in newborn infants than does morphine  The acute, severe pain of renal and biliary colic often requires a strong agonist opioid for adequate relief.  However, the drug-induced increase in smooth muscle tone may cause a paradoxical increase in pain secondary to increased spasm  An increase in the dose of opioid is usually successful in providing adequate analgesia. The relief produced by intravenous morphine in dyspnea from pulmonary edema associated with left ventricular failure is remarkable. Proposed mechanisms  include reduced anxiety (perception of shortness of breath)  reduced cardiac preload (reduced venous tone) and afterload (decreased peripheral resistance). Morphine can be particularly useful when treating painful myocardial ischemia with pulmonary edema.  Suppression of cough can be obtained at doses lower than those needed for analgesia. However, in recent years the use of opioid analgesics to allay cough has diminished largely because a number of effective synthetic compounds have been developed that are neither analgesic nor addictive.  Diarrhea from almost any cause can be controlled with the opioid analgesics  But if diarrhea is associated with infection appropriate chemotherapy. Must be given SHIVERING Although all opioid agonists have some propensity to reduce shivering, meperidine is reported to have the most pronounced anti- shivering properties. It is interesting that meperidine apparently blocks shivering through its action on subtypes of the a2 adrenoceptor.  The opioids are frequently used as premedicant drugs before anesthesia and surgery because of their  sedative  anxiolytic  analgesic  They are also used intraoperatively both as adjuncts to other anesthetic agents and, in high doses (eg, 0.02-0.075 mg/kg of fentanyl), as a primary component of the anesthetic regimen. Opioids are most commonly used in cardiovascular surgery and other types of high-risk surgery in which a primary goal is to minimize cardiovascular depression. In such situations, mechanical respiratory assistance must PROVIDED  Morphine is the most frequently used agent  low doses of local anesthetics in combination with fentanyl infused through a thoracic epidural catheter has also become an accepted method of pain control in patients recovering from major upper abdominal surgery.  Rectal suppositories of morphine and hydromorphone have long been used when oral and parenteral routes are undesirable.  The transdermal patch provides stable blood levels of drug and better pain control while avoiding the need for repeated parenteral injections.  Fentanyl has been the most successful opioid in transdermal application. The intranasal route avoids repeated parenteral drug injections and the first-pass metabolism of orally administered drugs. Another alternative to parenteral administration is the buccal transmucosal route, which uses a fentanyl citrate lozenge or a "lollipop" mounted on a stick.  Another type of pain control is now in widespread use for the management of breakthrough pain is PCA. With PCA, the patient controls a parenteral (usually intravenous) infusion device by depressing a button to deliver a preprogrammed dose of the desired opioid analgesic. There is a proven risk of respiratory depression with hypoxia that requires careful monitoring of vital signs and sedation level.  Direct toxic effects of the opioid analgesics that are extensions of their acute pharmacologic actions include respiratory depression nausea, vomiting constipation Tolerance and dependence  Intravenous injection of naloxone dramatically reverses coma due to opioid overdose but not that due to other CNS depressants. Use of the antagonist should not, of course, delay the institution of other therapeutic measures, especially respiratory support. 1. Use of pure agonists with weak partial agonists When a weak partial agonist such as pentazocine is given to a patient also receiving a full agonist (eg, morphine), there is a risk of diminishing analgesia or even inducing a state of withdrawal; combining full agonist with partial agonist opioids should be avoided. . Carbon dioxide retention caused by respiratory depression results in cerebral vasodilation . In patients with elevated intracranial pressure, this may lead to lethal alterations in brain function.  In pregnant women who are chronically using opioids, the fetus may become physically dependent in utero and manifest withdrawal symptoms in the early postpartum period. A daily dose as small as 6 mg of heroin (or equivalent) taken by the mother can result in a mild withdrawal syndrome in the infant, and twice that much may result in severe signs and symptoms, including irritability, shrill crying, diarrhea, or even seizures.  Inpatients with borderline respiratory reserve, the depressant properties of the opioid analgesics may lead to acute respiratory failure.  Because morphine and its congeners are metabolized primarily in the liver, their use in patients in prehepatic coma may be questioned. Half-life is prolonged in patients with impaired renal function, and morphine and its active glucuronide metabolite may accumulate; Dosage can often be reduced in such patients.  Patients with adrenal insufficiency (Addison's disease) and those with hypothyroidism (myxedema) may have prolonged and exaggerated responses to opioids.