08 Narcotic and non-narcotic analgesics

NARCOTIC AND NON-NARCOTIC ANALGESICS (Morphini hydrochloridum, Omnoponum, Codeini phosphas, Promedolum, Phentanylum, Pentazocini hydrichlorium, Tramadolum, Buprenorphinum, Nalorphini hydrochloridum, Naloxoni hydrochloridum, Naltrexonum, acidum acetylsalicilicum, analginum, Acidum mephenamicum, Paracetamolum, Ibuprophenum, Diclofenac-natrium, Indometacinum, Piroxicamum, Amisonum, Meloxicsm (Movalis), Celecoxib)

 

Narcotic and non-narcotic analgesics

Physiology of pain

The word “pain” comes from the Latin: poena meaning punishment, a fine, a penalty. Pain is an unpleasant sensation; nociception^[1] or nociperception^[2] is a measurable physiological event of a type usually associated with pain and agony and suffering. A sensation of pain can exist in the absence of nociception: it can occur in response to both external perceived events (for example, seeing something) or internal cognitive events (for example, the phantom limb pain of an amputee). Pain is defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” – International Association for the Study of Pain (IASP). Scientifically, pain (a subjective experience) is separate and distinct from nociception, the system which carries information, about inflammation, damage or near-damage in tissue, to the spinal cord and brain. Nociception frequently occurs without pain being felt and is below the level of consciousness. Despite it triggering pain and suffering, nociception is a critical component of the body‘s defense system. It is part of a rapid warning relay instructing the central nervous system to initiate motor neurons in order to minimize detected physical harm. Pain too is part of the body’s defense system; it triggers mental problem solving strategies that seek to end the painful experience, and it promotes learning, making repetition of the painful situation less likely.

Types of pain

Pain can be classified as acute or chronic. The distinction between acute and chronic pain is not based on its duration of sensation, but rather the nature of the pain itself. In general, physicians are more comfortable treating acute pain, which has as its source soft tissue damage, infection and/or inflammation.

Many physicians faced with patients who live with chronic pain have had no professional training in pain management. It is not regularly taught in medical school, and even recent legislation in some states to ensure that physicians receive continuing education in pain medicine and end-of-life care do not guarantee proper training in pain. In many states, there remains no legislation ensuring that licensed physicians, even those who work in hospital emergency rooms, have any pain management training whatsoever.

Chronic pain has no time limit, often has no apparent cause and serves no apparent biological purpose. Chronic pain can trigger multiple psychological problems that confound both patient and health care provider, leading to feelings of helplessness and hopelessness. The most common causes of chronic pain include low-back pain, headache, recurrent facial pain, cancer pain, and arthritic pain. Published information on pain perpetuate myths that do a disservice to those who live with pain and many glossaries contradict one another.

• Chronic pain was originally defined as pain that has lasted 6 months or longer. It is now defined as “the disease of pain.” Its origin, duration, intensity, and specific symptoms vary. The one consistent fact of chronic pain is that, as a disease, it cannot be understood in the same terms as acute pain, and the failure to make this distinction (particularly in those who suffer chronic pain) has been and continues to be the cause of multi-dimensional suffering, depression, social isolation, and helplessness.

The experience of physiological pain can be grouped according to the source and related nociceptors (pain detecting neurons).

• Cutaneous pain is caused by injury to the skin or superficial tissues. Cutaneous nociceptors terminate just below the skin, and due to the high concentration of nerve endings, produce a well-defined, localized pain of short duration. Examples of injuries that produce cutaneous pain include paper cuts, minor cuts, minor (first degree) burns and lacerations.

·        Somatic pain originates from ligaments, tendons, bones, blood vessels, and even nerves themselves. It is detected with somatic nociceptors. The scarcity of pain receptors in these areas produces a dull, poorly-localized pain of longer duration than cutaneous pain; examples include sprains and broken bones. Myofascial pain usually is caused by trigger points in muscles, tendons and fascia, and may be local or referred.

·        Visceral pain originates from body’s viscera, or organs. Visceral nociceptors are located within body organs and internal cavities. The even greater scarcity of nociceptors in these areas produces pain that is usually more aching and of a longer duration than somatic pain. Visceral pain is extremely difficult to localize, and several injuries to visceral tissue exhibit “referred” pain, where the sensation is localized to an area completely unrelated to the site of injury. Myocardial ischaemia (the loss of blood flow to a part of the heart muscle tissue) is possibly the best known example of referred pain; the sensation can occur in the upper chest as a restricted feeling, or as an ache in the left shoulder, arm or even hand. “The brain freeze” is another example of referred pain, in which the vagus nerve is cooled by cold inside the throat. Referred pain can be explained by the findings that pain receptors in the viscera also excite spinal cord neurons that are excited by cutaneous tissue. Since the braiormally associates firing of these spinal cord neurons with stimulation of somatic tissues in skin or muscle, pain signals arising from the viscera are interpreted by the brain as originating from the skin. The theory that visceral and somatic pain receptors converge and form synapses on the same spinal cord pain-transmitting neurons is called “Ruch’s Hypothesis”.

·        Phantom limb pain, a type of referred pain, is the sensation of pain from a limb that has been lost or from which a persoo longer receives physical signals. It is an experience almost universally reported by amputees and quadriplegics.

·        Neuropathic pain, can occur as a result of injury or disease to the nerve tissue itself. This can disrupt the ability of the sensory nerves to transmit correct information to the thalamus, and hence the brain interprets painful stimuli even though there is no obvious or known physiologic cause for the pain. Neuropathic pain is, as stated above, the disease of pain. It is not the sole definition for chronic pain, but does meet its criteria.

·        Antinociceptive pathways are activated when pain signals in the spinothalamic tract reach the brain stem and thalamus. The periaqueductal gray matter and nucleus raphe magnus release endorphins and enkephalins. A series of physicochemical changes then produce inhibition of pain transmission in the spinal cord.

·        70% of endorphin and enkephalin receptors are in the presynaptic membrane of nociceptors. Thus, most of the pain signal is stopped before it reaches the dorsal horn. The signal is then further weakened by dynorphin activity in the spinal cord. The site of action of various analgesics is shown.

·        Dynorphin activation of alpha receptors on inhibitory interneurons causes the release of GABA. This causes hyperpolarisation of dorsal horn cells and inhibits further transmission of the pain signal.

·        Major Sources of Pain

·         

·         

·        An analgesic (colloquially known as a painkiller) is any member of the diverse group of drugs used to relieve pain (achieve analgesia). This derives from Greek an–, “without”, and -algia, “pain”. Analgesic drugs act in various ways on the peripheral and central nervous system; they include paracetamol (acetaminophen), the nonsteroidal anti-inflammatory drugs (NSAIDs) such as the salicylates, narcotic drugs such as morphine, synthetic drugs with narcotic properties such as tramadol, and various others. Some other classes of drugs not normally considered analgesics are used to treat neuropathic pain syndromes; these include tricyclic antidepressants and anticonvulsants.

·        Opioid Analgesics—Morphine Type Source of opioids.

·        Narcotic and non-narcotic analgesics

·       

·        Pathway for sensation of pain and reaction to pain

·        Opiate agonists

·        History: References to the opium poppy exist as early as the third century BC with the Sumarians and Egyptians familiar with its analgesic and antidiarrheal properties. The opium poppy, papaver somniferum, actually contains more than 20 different alkaloids. Morphine was isolated in 1806 and followed by codeine in 1832. In an effort to create a strong analgesic with no physical dependence-inducing properties, meperidine and methadone were introduced in 1942 and 1947, respectively. Unfortunately, neither compound met this need.

·       

·        Nalorphine, released in 1952 and used to treat opiate toxicity, is a stronger opiate antagonist than agonist. Nalorphine has since been discontinued due to the high incidence of psychometric side effects and the release of relatively “pure” opiate antagonists, naloxone (1971), naltrexone (1984), and nalmefene (1995).

·        With the confirmation of opiate receptors, the search began for endogenous opiates. In 1975, Hughes and colleagues[267] published their isolation of encephalin, a pentapeptide that was later determined to possess an amino acid sequence similar to a section of beta-endorphin. Both encephalin and beta-endorphin are now known to exert opiate-agonist properties.

·        Mechanism of Action: Opiate agonists and antagonists interact with stereospecific, saturable receptors in the brain and other tissues. These receptors are widely but unevenly distributed throughout the CNS. Opiate receptors include µ (mu), kappa (kappa), and delta (delta), which have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (µ). Distribution of these receptors varies according to the presence in the CNS. Mu receptors are located widely throughout the CNS, especially in the limbic system (frontal cortex, temporal cortex, amygdala, and hippocampus); thalamus; striatum; hypothalamus; and midbrain. Kappa receptors are located primarily in the spinal cord and cerebral cortex. Opiate receptors are coupled with G-protein (guanine-nucleotide-binding protein) receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Opiate agonists produce analgesia by inhibiting excitatory neurotransmission of substance P, acetylcholine, noradrenaline, dopamine, and GABA on a cellular level by blocking voltage-dependent calcium channels. Opiate agonists also have stimulatory effects oeurotransmission and neurotransmitter release; the exact mechanism of this stimulation has not been fully determined. Analgesia is mediated through changes in the perception of pain at the spinal cord (µ2-, delta-, kappa-receptors) and higher levels in the CNS (µ1- and kappa3 receptors). Opiate agonists also modulate the endocrine and immune systems. Opioids inhibit the release of vasopressin, somatostatin, insulin and glucagon.[1939] In addition to analgesia, stimulation at the µ-receptor produces euphoria, respiratory depression, and physical dependence.

·       

·        Distinguishing Features: Pure opiate agonists may be categorized as phenanthrenes including codeine, hydromorphone, morphine, and oxycodone; phenylpiperidines (alfentanil, fentanyl, meperidine, and sufentanil) and diphenylheptanes (methadone, propoxyphene). Pure opiate agonists are generally referred to as either strong opiates (hydromorphone, morphine, methadone, and oxycodone) and weak opiate agonists (codeine, hydrocodone, and propoxyphene).

·         

·        Naloxone, naltrexone, and nalmefene are antagonists at µ- and kappa-receptors. Administration of these agents to patients taking chronic opiate agonists will induce withdrawal symptoms and cause pain to recur.

·        Published tables vary in suggested equianalgesic doses of pure opiate agonists. Assessment of individual clinical response is necessary because there is not complete cross-tolerance among these agents.

·        Opiate Agonist Equianalgesic Chart – Adults and Children >= 50 kg

·        Morphine (round-the-clock dosing)

·        •Oral 30 mg

·        •Parenteral 10 mg

·        Morphine (single or intermittent dosing)

·        •Oral 60 mg

·        •Parenteral 10 mg

·        Hydromorphone

·        •Oral 7.5 mg

·        •Parenteral 1.5 mg

·        Meperidine

·        •Oral 300 mg

·        •Parenteral 75-100 mg

·        Levorphanol

·        •Oral 4 mg

·        •Parenteral 1-2 mg

·        Oxycodone

·        •Oral 15-20 mg

·        Hydrocodone

·        •Oral 30 mg

·        Codeine

·        •Oral 200 mg (this dose is not recommended)

·        •Parenteral: This dosage form is not routinly used clinically as more potent and less toxic agents are available.

·        Some pharmacokinetic differences also exist. Opiate agonists may be administered via many routes including orally, parenterally, epidurally, intrathecally, and topically. Meperidine is a short-acting opiate agonist, while methadone is a long-acting opiate agonist. Levomethadyl, a drug for the management of opiate dependence, acts longer than methadone. Regarding opiate antagonists, both naloxone and nalmefene are administered intravenously, however, naloxone is short-acting (1-2 hours) and nalmefene is long-acting (10 hours). Naltrexone is administered orally and is long-acting.

·        Meperidine also possesses the unique ability to interrupt amphotericin-B-induced infusion reactions such as shaking chills. It is unclear how meperidine mediates this effect, since other opiate agonists are not known to be effective for this use.

·        Opiate dependence is considered a medical disorder requiring pharmacologic treatment. During addiction, the functioning of the opiate receptor is altered due to repeated opiate exposure. Methadone treatment normalizes neurologic and endocrine processes.

·        Opium is still available as a tincture or as camphorated opium tincture (Paregoric) that is used to control severe diarrhea. Paregaoric is 25 times less potent than opium tincture. According to the American Academy of Pediatrics, diluted tincture of opium is the preferred drug for the treatment of opioid withdrawal ieonates.

·       

·        Adverse Reactions: The most significant and well-known adverse reaction to opiate agonists is respiratory depression. Death secondary to opiate overdose is nearly always due to respiratory depression. When opiate agonists are appropriately titrated, the risk of severe respiratory depression is generally small as tolerance rapidly develops to this effect. True allergy to opiate agonists is uncommon, despite the claims of many patients. Opiate agonists can cause histamine release, which can induce rash and pruritus. The most common GI effects include nausea/vomiting and constipation. Nausea/vomiting is more common at the initiation of therapy or when increasing doses and usually resolves within a few days. Constipation is an ongoing concern with chronic opiate therapy and requires prophylactic treatment. Codeine is often associated GI intolerance, which some patients incorrectly identify as an allergic reaction.

·        Some health care professionals avoid opiate agonists therapy for the treatment of pain due to concerns of physical and psychological dependence and tolerance. It is important to differentiate physiologic dependence, the onset of a withdrawal syndrome upon abrupt discontinuation of the drug from psychological dependence. Psychological dependence is a behavioral syndrome characterized by drug craving, overwhelming concern with acquisition of the drug and other drug-related behaviors such as drug selling and seeking the drug from multiple sources. Tolerance is the need for increasing opiate doses to maintain initial pain relief. Typically, tolerance presents as a decrease in the duration of analgesia and is managed by increasing the opioid dose or frequency. There is no limit to tolerance; thus, some patients may require very large doses of opiate analgesics to control their pain. When increasing doses of analgesia are required causes may be multi-factorial including tolerance, progression of disease or psychological distress.

·        Clinicians should be aware of a CNS-excitatory metabolite of meperidine and propoxyphene. When administered in high doses, especially to patients with renal disease, these agents can cause CNS disturbances including seizures.

·        ixed opiate agonists/antagonists

·         

·        History: In an effort to develop opioid analgesics with little or no abuse potential, agents with both opiate agonist and antagonist activities have been developed. With the introduction of pentazocine (1967), butorphanol (1978), nalbuphine (1979), and buprenorphine (1981), the group of mixed agonist-antagonist opiate analgesics was born. The first marketed mixed agonist/antagonist, nalorphine (1952) is no longer available due to an unacceptable incidence of psychotomimetic effects. Investigational mixed opiate agonists/antagonists include meptazinol, profadol, and propiram.

·         Mechanism of Action: Opiate agonists and antagonists interact with stereospecific, saturable receptors in the brain and other tissues. Opiate receptors include µ (mu), kappa (kappa), and delta (delta), which have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (µ). These receptors are widely but unevenly distributed throughout the CNS. Mu receptors are located in all areas of the CNS, especially in the limbic system (frontal cortex, temporal cortex, amygdala, and hippocampus); thalamus; striatum; hypothalamus; and midbrain. Kappa receptors are located primarily in the spinal cord and cerebral cortex. Opiate receptors are coupled with G-protein (guanine-nucleotide-binding protein) receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins activated effector proteins. Analgesia is mediated through changes in the perception of pain at the spinal cord (µ2-, delta-, kappa-receptors) and higher levels in the CNS (µ1- and kappa3 receptors). In addition to analgesia, stimulation at the µ-receptor produces euphoria, respiratory depression, and physical dependence. The opiate agonists/antagonists are thought to bind to µ-receptors and compete with pure opiate agonists, but either exert no action (competitive antagonism) or limited effects (partial agonist) at this receptor. It is possible that an opioid may function as an antagonist at the µ-receptor but still have analgesic effects by functioning as an agonist at kappa-receptors.

·         Distinguishing Features: Mixed opiate agonists/antagonists exhibit a variety of actions at the three receptors, although all are antagonists at the µ-receptor and most are either full or partial agonists at kappa-receptors. The mixed opiate agonists/antagonists may be divided into two groups based upon their adverse effects and abstinence syndromes. Morphine-type opiate agonists/antagonists have low intrinsic µ-agonist activity but have a high affinity for the µ-receptor. Buprenorphine, which has partial µ-agonist activity, and the investigational agents, meptazinol, profadol and propiram, are members of this group. Buprenorphine produces analgesia and other CNS effects that are qualitatively similar to morphine. The withdrawal syndrome associated with buprenorphine is less severe than that of morphine. Nalorphine-type opiate agonists/antagonists have varying affinity and intrinsic activity at all three opiate receptors, but all are competitive antagonists at the µ-receptor with agonist activity at kappa-receptors. Members of this group include butorphanol, nalbuphine, and pentazocine. These agents are associated with a higher incidence of psychotomimetic effects.

·        Unlike pure opiate agonists, these agents have a ceiling effect in regard to analgesic effects and respiratory depression. Mixed opiate agonists/antagonists are generally not considered agents of choice in patients with chronic pain. These agents can precipitate withdrawal symptoms in patients who are taking chronic opiate agonists.

·        Adverse Reactions: The abuse potential of the mixed opiate agonists/antagonists is less than propoxyphene and codeine. The respiratory depressive effects of the mixed opiate agonists/antagonists seem to have a ceiling effect as opposed to pure opiate agonists where this effect is proportional to the dose. Buprenorphine-induced respiratory depression is not readily reversed by usual doses of naloxone; large doses of naloxone must be used. High doses of pentazocine are associated with respiratory depression, hypertension, tachycardia and psychotomimetic effects including anxiety, nightmares, and hallucinations. The hemodynamic effects of mixed opiate agonists/antagonists are varied. The incidence of biliary tract effects with these agents is usually lower than the incidence of biliary side effects with morphine.

·         

·        Tolerance may develop to the analgesic and certain adverse effects of mixed agonists/antagonists, although not to the degree of that seen with pure opiate agonists.

·        Narcotics

·        Those drugs which possess both an analgesic (pain relieving) and sedative properties.

·        OPIOID

·        refer to drugs in a generic sense, natural or synthetic, with morphine- like actions

·        Classification of OPIOIDS

·                  natural        

·                  semisynthetic        

·                  synthetic     

·        Natural

·        phenanthrene

·                 

morphine 10%     

·                  codeine 0.5%       

·                  thebaine 0.2%      

·        benzylisoquioline

·                 

papaverine  

·                  noscopine   

·                  narceine      

·        Semisynthetic

·                  heroin         

·                  oxymorphone       

·                  hydromorphone

·                 

·        Synthetic

·                  meperidine 

·                  methadone  

·                  morphinians         

·                  benzamorphans

·        Morphine

·                  pentacyclic alkaloid (five ring structure)      

·                  oxygen bridge at 4,5 position  

·                  three major rings (a, b, c)         

·                  phenolic groups (s/a hydroxyl, alcoholic, OH) at position 3 and 6         

·                  modifications at those positions changes pharmacokinetics and potency of drug   

·                  nitrogen at 16 position (n16)   

·                  changing it by adding an alkyl group converts it to naloxone (i.e. go from a agonist to an antagonist)    

·        OPIOID receptors (located in CNS)

·        Receptor Stimulation

·        mu

Mode of action of opioids. Most neurons react to opioids with hyperpolarization, reflecting an increase in K+ conductance. Ca2+ influx into nerve terminals during excitation is decreased, leading to a decreased release of excitatory transmitters and decreased synaptic activity (A). Depending on the cell population affected, this synaptic inhibition translates into a depressant or excitant effect (B).

Effects of opioids (B). The analgesic effect results from actions at the level of the spinal cord (inhibition of nociceptive impulse transmission) and the brain (attenuation of impulse spread, inhibition of pain perception). Attention and ability to concentrate are impaired. There is a mood change, the direction of which depends on the initial condition. Aside from the relief associated with the abatement of strong pain, there is a feeling of detachment (floating sensation) and sense of well-being (euphoria), particularly after intravenous injection and, hence, rapid buildup of drug levels in the brain. The desire to re-experience this state by renewed administration of drug may become overpowering: development of psychological dependence. The atttempt to quit repeated use of the drug results in withdrawal signs of both a physical (cardiovascular disturbances) and psychological (restlessness, anxiety, depression) nature. Opioids meet the criteria of “addictive” agents, namely, psychological and physiological dependence as well as a compulsion to increase the dose. For these reasons, prescription of opioids is subject to special rules (Controlled Substances Act, USA; Narcotic Control Act, Canada; etc). Regulations specify, among other things, maximum dosage (permissible single dose, daily maximal dose, maximal amount per single prescription). Prescriptions need to be issued on special forms the completion of which is rigorously monitored. Certain opioid analgesics, such as codeine and tramadol, may be prescribed in the usual manner, because of their lesser potential for abuse and development of dependence. Differences between opioids regarding efficacy and potential for dependence probably reflect differing affinity and intrinsic activity profiles for the individual receptor subtypes. A given sustance does not necessarily behave as an agonist or antagonist at all receptor subtypes, but may act as an agonist at one subtype and as a partial agonist/ antagonist or as a pure antagonist at another. The abuse potential is also determined by kinetic properties, because development of dependence is favored by rapid build-up of brain concentrations. With any of the high-efficacy opioid analgesics, overdosage is likely to result in respiratory paralysis (impaired sensitivity of medullary chemoreceptors to CO2). The maximally possible extent of respiratory depression is thought to be less in partial agonist/ antagonists at opioid receptors (pentazocine, nalbuphine). The cough-suppressant (antitussive) effect produced by inhibition of the cough reflex is independent of the effects on nociception or respiration (antitussives: codeine. noscapine). Stimulation of chemoreceptors in the area postrema results in vomiting, particularly after first-time administration or in the ambulant patient. The emetic effect disappears with repeated use because a direct inhibition of the emetic center then predominates, which overrides the stimulation of area postrema chemoreceptors. Opioids elicit pupillary narrowing (miosis) by stimulating the parasympathetic portion (Edinger-Westphal nucleus) of the oculomotor nucleus. Peripheral effects concern the motility and tonus of gastrointestinal smooth muscle; segmentation is enhanced, but propulsive peristalsis is inhibited. The tonus of sphincter muscles is raised markedly. In this fashion, morphine elicits the picture of spastic constipation. The antidiarrheic effect is used therapeutically (loperamide). Gastric emptying is delayed (pyloric spasm) and drainage of bile and pancreatic juice is impeded, because the sphincter of Oddi contracts. Likewise, bladder function is affected; specifically bladder emptying is impaired due to increased tone of the vesicular sphincter. Uses: The endogenous opioids (metenkephalin, leuenkephalin, в-endorphin) cannot be used therapeutically because, due to their peptide nature, they are either rapidly degraded or excluded from passage through the bloodbrain barrier, thus preventing access to their sites of action even after parenteral administration (A). Morphine can be given orally or parenterally, as well as epidurally or intrathecally in the spinal cord. The opioids heroin and fentanyl are highly lipophilic, allowing rapid entry into the CNS. Because of its high potency, fentanyl is suitable for transdermal delivery (A). In opiate abuse, “smack” (“junk,” “jazz,” “stuff,” “China white;” mostly heroin) is self administered by injection (“mainlining”) so as to avoid first-pass metabolism and to achieve a faster rise in brain concentration.

Evidently, psychic effects (“kick,” “buzz,” “rush”) are especially intense with this route of administration. The user may also resort to other more unusual routes: opium can be smoked, and heroin can be taken as snuff (B).

Metabolism (C). Like other opioids bearing a hydroxyl group, morphine is conjugated to glucuronic acid and eliminated renally. Glucuronidation of the OH-group at position 6, unlike that at position 3, does not affect affinity. The extent to which the 6-glucuronide contributes to the analgesic action remains uncertain at present. At any rate, the activity of this polar metabolite needs to be taken into account in renal insufficiency (lower dosage or longer dosing interval).

Tolerance. With repeated administration of opioids, their CNS effects can lose intensity (increased tolerance). In the course of therapy, progressively larger doses are needed to achieve the same degree of pain relief. Development of tolerance does not involve the peripheral effects, so that persistent constipation during prolonged use may force a discontinuation of analgesic therapy however urgently needed. Therefore, dietetic and pharmacological measures should be taken prophylactically to prevent constipation, whenever prolonged administration of opioid drugs is indicated.

Morphine antagonists and partial agonists. The effects of opioids can be

abolished by the antagonists naloxone or naltrexone (A), irrespective of the receptor type involved. Given by itself, neither has any effect iormal subjects; however, in opioid-dependent subjects, both precipitate acute withdrawal signs.

Because of its rapid presystemic elimination, naloxone is only suitable for parenteral use. Naltrexone is metabolically more stable and is given orally. Naloxone is effective as antidote in the treatment of opioid-induced respiratory paralysis. Since it is more rapidly eliminated than most opioids, repeated doses may be needed. Naltrexone may be used asan adjunct in withdrawal therapy. Buprenorphine behaves like a partial agonist/antagonist at µ-receptors. Pentazocine is an antagonist at µ-receptors and an agonist at к-receptors (A). Both are classified as “low-ceiling” opioids (B), because neither is capable of eliciting the maximal analgesic effect obtained with morphine or meperidine. The antagonist action of partial agonists may result in an initial decrease in effect of a full agonist during changeover to the latter. Intoxication with buprenorphine cannot be reversed with antagonists, because the drug dissociates only very slowly from the opioid receptors and competitive occupancy of the receptors cannot be achieved as fast as the clinical situation demands.

 

Opioids in chronic pain: In the management of chronic pain, opioid plasma concentration must be kept continuously in the effective range, because a fall below the critical level would cause the patient to experience pain. Fear of this situation would prompt intake of higher doses thaecessary. Strictly speaking, the aim is a prophylactic analgesia.

Like other opioids (hydromorphone, meperidine, pentazocine, codeine), morphine is rapidly eliminated, limiting its duration of action to approx. 4 h. To maintain a steady analgesic effect, these drugs need to be given every 4 h. Frequent dosing, including at nighttime, is a major inconvenience for chronic pain patients. Raising the individual dose would permit the dosing interval to be lengthened; however, it would also lead to transient peaks above the therapeutically required plasma level with the attending risk of unwanted toxic effects and tolerance development. Preferred alternatives include the use of controlled-release preparations of morphine, a fentanyl adhesive patch, or a longer-acting opioid such as l-methadone. The kinetic properties of the latter, however, necessitate adjustment of dosage in the course of treatment, because low dosage during the first days of treatment fails to provide pain relief, whereas high dosage of the drug, if continued, will lead to accumulation into a toxic concentration range (C). When the oral route is unavailable opioids may be administered by continuous infusion (pump) and when appropriate under control by the patient – advantage: constant therapeutic plasma level; disadvantage: indwelling catheter. When constipation becomes intolerable morphin can be applied near the spinal cord permitting strong analgesic effect at much lower total dosage.

 

Narcotic and non-narcotic analgesics

Pathway for sensation of pain and reaction to pain

Opiate agonists

History: References to the opium poppy exist as early as the third century BC with the Sumarians and Egyptians familiar with its analgesic and antidiarrheal properties. The opium poppy, papaver somniferum, actually contains more than 20 different alkaloids. Morphine was isolated in 1806 and followed by codeine in 1832. In an effort to create a strong analgesic with no physical dependence-inducing properties, meperidine and methadone were introduced in 1942 and 1947, respectively. Unfortunately, neither compound met this need.

 

Nalorphine, released in 1952 and used to treat opiate toxicity, is a stronger opiate antagonist than agonist. Nalorphine has since been discontinued due to the high incidence of psychometric side effects and the release of relatively “pure” opiate antagonists, naloxone (1971), naltrexone (1984), and nalmefene (1995).

With the confirmation of opiate receptors, the search began for endogenous opiates. In 1975, Hughes and colleagues[267] published their isolation of encephalin, a pentapeptide that was later determined to possess an amino acid sequence similar to a section of beta-endorphin. Both encephalin and beta-endorphin are now known to exert opiate-agonist properties.

Mechanism of Action: Opiate agonists and antagonists interact with stereospecific, saturable receptors in the brain and other tissues. These receptors are widely but unevenly distributed throughout the CNS. Opiate receptors include µ (mu), kappa (kappa), and delta (delta), which have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (µ). Distribution of these receptors varies according to the presence in the CNS. Mu receptors are located widely throughout the CNS, especially in the limbic system (frontal cortex, temporal cortex, amygdala, and hippocampus); thalamus; striatum; hypothalamus; and midbrain. Kappa receptors are located primarily in the spinal cord and cerebral cortex. Opiate receptors are coupled with G-protein (guanine-nucleotide-binding protein) receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Opiate agonists produce analgesia by inhibiting excitatory neurotransmission of substance P, acetylcholine, noradrenaline, dopamine, and GABA on a cellular level by blocking voltage-dependent calcium channels. Opiate agonists also have stimulatory effects oeurotransmission and neurotransmitter release; the exact mechanism of this stimulation has not been fully determined. Analgesia is mediated through changes in the perception of pain at the spinal cord (µ2-, delta-, kappa-receptors) and higher levels in the CNS (µ1- and kappa3 receptors). Opiate agonists also modulate the endocrine and immune systems. Opioids inhibit the release of vasopressin, somatostatin, insulin and glucagon.[1939] In addition to analgesia, stimulation at the µ-receptor produces euphoria, respiratory depression, and physical dependence.

 

Distinguishing Features: Pure opiate agonists may be categorized as phenanthrenes including codeine, hydromorphone, morphine, and oxycodone; phenylpiperidines (alfentanil, fentanyl, meperidine, and sufentanil) and diphenylheptanes (methadone, propoxyphene). Pure opiate agonists are generally referred to as either strong opiates (hydromorphone, morphine, methadone, and oxycodone) and weak opiate agonists (codeine, hydrocodone, and propoxyphene).

 

Naloxone, naltrexone, and nalmefene are antagonists at µ- and kappa-receptors. Administration of these agents to patients taking chronic opiate agonists will induce withdrawal symptoms and cause pain to recur.

Published tables vary in suggested equianalgesic doses of pure opiate agonists. Assessment of individual clinical response is necessary because there is not complete cross-tolerance among these agents.

Opiate Agonist Equianalgesic Chart – Adults and Children >= 50 kg

Morphine (round-the-clock dosing)

•Oral 30 mg

•Parenteral 10 mg

Morphine (single or intermittent dosing)

•Oral 60 mg

•Parenteral 10 mg

Hydromorphone

•Oral 7.5 mg

•Parenteral 1.5 mg

Meperidine

•Oral 300 mg

•Parenteral 75-100 mg

Levorphanol

•Oral 4 mg

•Parenteral 1-2 mg

Oxycodone

•Oral 15-20 mg

Hydrocodone

•Oral 30 mg

Codeine

•Oral 200 mg (this dose is not recommended)

•Parenteral: This dosage form is not routinly used clinically as more potent and less toxic agents are available.

Some pharmacokinetic differences also exist. Opiate agonists may be administered via many routes including orally, parenterally, epidurally, intrathecally, and topically. Meperidine is a short-acting opiate agonist, while methadone is a long-acting opiate agonist. Levomethadyl, a drug for the management of opiate dependence, acts longer than methadone. Regarding opiate antagonists, both naloxone and nalmefene are administered intravenously, however, naloxone is short-acting (1-2 hours) and nalmefene is long-acting (10 hours). Naltrexone is administered orally and is long-acting.

Meperidine also possesses the unique ability to interrupt amphotericin-B-induced infusion reactions such as shaking chills. It is unclear how meperidine mediates this effect, since other opiate agonists are not known to be effective for this use.

Opiate dependence is considered a medical disorder requiring pharmacologic treatment. During addiction, the functioning of the opiate receptor is altered due to repeated opiate exposure. Methadone treatment normalizes neurologic and endocrine processes.

Opium is still available as a tincture or as camphorated opium tincture (Paregoric) that is used to control severe diarrhea. Paregaoric is 25 times less potent than opium tincture. According to the American Academy of Pediatrics, diluted tincture of opium is the preferred drug for the treatment of opioid withdrawal ieonates.

Adverse Reactions: The most significant and well-known adverse reaction to opiate agonists is respiratory depression. Death secondary to opiate overdose is nearly always due to respiratory depression. When opiate agonists are appropriately titrated, the risk of severe respiratory depression is generally small as tolerance rapidly develops to this effect. True allergy to opiate agonists is uncommon, despite the claims of many patients. Opiate agonists can cause histamine release, which can induce rash and pruritus. The most common GI effects include nausea/vomiting and constipation. Nausea/vomiting is more common at the initiation of therapy or when increasing doses and usually resolves within a few days. Constipation is an ongoing concern with chronic opiate therapy and requires prophylactic treatment. Codeine is often associated GI intolerance, which some patients incorrectly identify as an allergic reaction.

Some health care professionals avoid opiate agonists therapy for the treatment of pain due to concerns of physical and psychological dependence and tolerance. It is important to differentiate physiologic dependence, the onset of a withdrawal syndrome upon abrupt discontinuation of the drug from psychological dependence. Psychological dependence is a behavioral syndrome characterized by drug craving, overwhelming concern with acquisition of the drug and other drug-related behaviors such as drug selling and seeking the drug from multiple sources. Tolerance is the need for increasing opiate doses to maintain initial pain relief. Typically, tolerance presents as a decrease in the duration of analgesia and is managed by increasing the opioid dose or frequency. There is no limit to tolerance; thus, some patients may require very large doses of opiate analgesics to control their pain. When increasing doses of analgesia are required causes may be multi-factorial including tolerance, progression of disease or psychological distress.

Clinicians should be aware of a CNS-excitatory metabolite of meperidine and propoxyphene. When administered in high doses, especially to patients with renal disease, these agents can cause CNS disturbances including seizures.

ixed opiate agonists/antagonists

 

History: In an effort to develop opioid analgesics with little or no abuse potential, agents with both opiate agonist and antagonist activities have been developed. With the introduction of pentazocine (1967), butorphanol (1978), nalbuphine (1979), and buprenorphine (1981), the group of mixed agonist-antagonist opiate analgesics was born. The first marketed mixed agonist/antagonist, nalorphine (1952) is no longer available due to an unacceptable incidence of psychotomimetic effects. Investigational mixed opiate agonists/antagonists include meptazinol, profadol, and propiram.

 

Mechanism of Action: Opiate agonists and antagonists interact with stereospecific, saturable receptors in the brain and other tissues. Opiate receptors include µ (mu), kappa (kappa), and delta (delta), which have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (µ). These receptors are widely but unevenly distributed throughout the CNS. Mu receptors are located in all areas of the CNS, especially in the limbic system (frontal cortex, temporal cortex, amygdala, and hippocampus); thalamus; striatum; hypothalamus; and midbrain. Kappa receptors are located primarily in the spinal cord and cerebral cortex. Opiate receptors are coupled with G-protein (guanine-nucleotide-binding protein) receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins activated effector proteins. Analgesia is mediated through changes in the perception of pain at the spinal cord (µ2-, delta-, kappa-receptors) and higher levels in the CNS (µ1- and kappa3 receptors). In addition to analgesia, stimulation at the µ-receptor produces euphoria, respiratory depression, and physical dependence. The opiate agonists/antagonists are thought to bind to µ-receptors and compete with pure opiate agonists, but either exert no action (competitive antagonism) or limited effects (partial agonist) at this receptor. It is possible that an opioid may function as an antagonist at the µ-receptor but still have analgesic effects by functioning as an agonist at kappa-receptors.

Distinguishing Features: Mixed opiate agonists/antagonists exhibit a variety of actions at the three receptors, although all are antagonists at the µ-receptor and most are either full or partial agonists at kappa-receptors. The mixed opiate agonists/antagonists may be divided into two groups based upon their adverse effects and abstinence syndromes. Morphine-type opiate agonists/antagonists have low intrinsic µ-agonist activity but have a high affinity for the µ-receptor. Buprenorphine, which has partial µ-agonist activity, and the investigational agents, meptazinol, profadol and propiram, are members of this group. Buprenorphine produces analgesia and other CNS effects that are qualitatively similar to morphine. The withdrawal syndrome associated with buprenorphine is less severe than that of morphine. Nalorphine-type opiate agonists/antagonists have varying affinity and intrinsic activity at all three opiate receptors, but all are competitive antagonists at the µ-receptor with agonist activity at kappa-receptors. Members of this group include butorphanol, nalbuphine, and pentazocine. These agents are associated with a higher incidence of psychotomimetic effects.

Unlike pure opiate agonists, these agents have a ceiling effect in regard to analgesic effects and respiratory depression. Mixed opiate agonists/antagonists are generally not considered agents of choice in patients with chronic pain. These agents can precipitate withdrawal symptoms in patients who are taking chronic opiate agonists.

 

Adverse Reactions: The abuse potential of the mixed opiate agonists/antagonists is less than propoxyphene and codeine. The respiratory depressive effects of the mixed opiate agonists/antagonists seem to have a ceiling effect as opposed to pure opiate agonists where this effect is proportional to the dose. Buprenorphine-induced respiratory depression is not readily reversed by usual doses of naloxone; large doses of naloxone must be used. High doses of pentazocine are associated with respiratory depression, hypertension, tachycardia and psychotomimetic effects including anxiety, nightmares, and hallucinations. The hemodynamic effects of mixed opiate agonists/antagonists are varied. The incidence of biliary tract effects with these agents is usually lower than the incidence of biliary side effects with morphine.

 

Tolerance may develop to the analgesic and certain adverse effects of mixed agonists/antagonists, although not to the degree of that seen with pure opiate agonists.

Narcotics

Those drugs which possess both an analgesic (pain relieving) and sedative properties.

OPIOID receptors to drugs in a generic sense, natural or synthetic, with morphine- like actions

Classification of OPIOIDS

          natural        

          semisynthetic        

          synthetic     

Natural

phenanthrene

         

morphine 10%     

          codeine 0.5%       

          thebaine 0.2%      

benzylisoquioline

         

papaverine  

          noscopine   

          narceine      

Semisynthetic

          heroin         

          oxymorphone       

          hydromorphone

         

Synthetic

          meperidine 

          methadone  

          morphinians         

          benzamorphans

Morphine

          pentacyclic alkaloid (five ring structure)      

          oxygen bridge at 4,5 position  

          three major rings (a, b, c)         

          phenolic groups (s/a hydroxyl, alcoholic, OH) at position 3 and 6     

          modifications at those positions changes pharmacokinetics and potency of drug       

          nitrogen at 16 position (n16)   

          changing it by adding an alkyl group converts it to naloxone (i.e. go from a agonist to an antagonist)        

OPIOID receptors (located in CNS)

Receptor Stimulation

mu

          physical dependence      

          euphoria     

          analgesia (supraspinal)   

          respiratory depression    

kappa

          sedation      

          analgesia (spinal)  

          miosis         

delta

         

analgesia (spinal & supraspinal)        

          release of growth hormone      

sigma

          dysphoria (opposite of euphoria)       

          hallucination         

          respiratory and vasomotor stimulation         

          mydriasis

OPIOID receptors in CNS, their distribution is not uniform they are at areas concerned with pain receptor locations beginning with highest concentration areas

1. cerebral cortex

2. amygdala

3. septum

4. thalamus

5. hypothalamus

6. midbrain

7. spinal cord

 

Sigma receptor also known as the “pcp receptor” since pcp will bind there

Mu receptor high in areas of pain perception and at medulla (area for respiration)

 

Amino acid sequence of OPIOID peptides

In early 1950’s, it was thought that since morphine from poppy plant had relieved pain then it was likely that their was an endogenous substance for pain relief first found the receptor and then found the peptide which are enkephalins

Enkephalins

          they are 5 amino acids long     

          also have met enkephalin (methionine at 5′ position) and leu enkephalin (leucine at 5′ position      enkephalins are neuromodulators since they are small peptides, it was found that they came from larger peptides (pro enkephalins) proenkephalin gene codes for peptide 276 amino acid in length cleavage of proenkephalin gives 4 to 5 pieces of activated enkephalins

          Runners high enkephalins let a runner not feel the knee pains caused by running

Endorphin   30 amino acid peptide    

          last 5 amino acids are the same sequence as enkephalins 

          endorphins are neurohormones

          conservation between species   

          little difference in humans

Proopomelanocortin

          various proteins that can come from this gene       

          gamma MSH, ACTH, beta LPH, alpha MSH, beta MSH, met Enk

Pharmacokinetics

absorption

          readily absorbed from GI tract, nasal mucosa, lung subcutaneous, intramuscular, and intravenous route 

          distribution 

          bound free morphine accumulates in kidney, lung, liver, and spleen  

          CNS is primary site of action (sedation)      

metabolism/excretion

          metabolic transformation in liver       

          conjugation with glucuronic acid       

          excreted by kidney         

          half life is 2.5 to 3 hours (does not persist in body tissue)         

          morphine 3 glucuronide in main excretion product         

          lose 90% in first day      

          duration of 10 mg dose is 3 to 5 hours        

Morphine administration

          oral morphine not given due to erratic oral availability    

          significant variable first pass effect from person to person and have intraspecies effect (same dose will vary in person day to day)  

          IV morphine acts promptly and its main effect is at the CNS

CNS is primary site of action of morphine

          analgesia     

          sedation      

          euphoria     

          mood change        

          mental cloudiness

          Morphine strongest analgesic today as a natural substance

Morphine analgesia

          changes our reaction and our perception of pain   

i.e. if person steps on your foot, still perceive somebody stepped on foot, but have lesser of a sensation where paiot blocked, but your reaction changes where your pain threshold has increased (i.e. can tolerate pain more)

          severe cancer pain is tolerated more when person is given morphine  

          relieves all types of pain, but most effective against continuous dull aching pain 

          sharp, stabbing, shooting pain also relieved by morphine

 

         Morphine sedation

          morphine causes sedation effect, but no loss of consciousness  

          person easily go asleep, but easily aroused unlike when on barbiturates where person goes into coma

          Morphine euphoria

          sense of well being         

          reason why morphine is abused

 

          Morphine given to a pain free individual

          first experience is dysphoria    

          not experienced in person in pain

Initial Injection of opioid makes person sick, have anxiety, apathetic, lethargic, inability to concentrate, nausea, vomiting, and drowsiness Morphine mood change person who is lively will become dull when using morphine

Morphine mental cloudiness difficulty in concentration and have apathy

Effects of morphine on respiration there is a primary and continuous depression of respiration related to dose decrease rate decrease volume      decrease tidal exchange     mu receptor activation produces respiratory depression; with increase in dose, further respiratory depression Morphine CNS becomes less responsive to pCO2 thereby causing a build up of CO2

Depression on medulla affect brain center on rhythm and responsiveness gives irregular breathing patterns. As increase dose, one will see periods of apnea Respiratory centers less responsive to pCO2 as well as medullary centers for responsiveness to CO2 in blood so irregular breathing (short breath) normal response 2 to 3 hours after normal dose Morphine initially stimulates chemoreceptor trigger zone (CTZ)and then it will depress CTZ (antiemetic effect) this may be one of the reasons for the dysphoria in pain free people

Morphine nausea and vomiting

          morphine initially stimulates the CTZ -> emetic    

          later effect is antiemetic  

cough reflex

          antitussive effect due to direct depression of cough center in the medulla         

pupil size

          morphine produces miosis (pinpoint pupils)

          tolerance does not develop to miosis  

excitatory and spinal reflexes

          high doses of many OPIOID cause convulsions

         

Central trigger zone

          in postrema of medulla   

          stimulation by stretch receptors causes nausea and vomiting     

          has afferents from gut and ear  

          involved in motion sickness     

Codeine in cough syrup

          it has an antitussive effect        

Morphine and all OPIOID

          they cause miosis (pinpoint pupils)    

          kappa receptor effect      

          gives indication that patient has OPIOID overdose

          pinpoint pupils responsive to bright light    

          if block kappa receptor (causes miosis), see mydriasis from sigma effect         

          oculomotor nerve (CN3) is stimulated by kappa receptor site   

          start at edenmeyeroff nucleus. see parasympathetic discharge at oculomotor nerve giving pin point pupils    

          atropine only blocks effect indicating parasympathetics only partially explains the miosis

High doses (overdose situation) of morphine

          can cause convulsions    

          this is stimulation at sigma receptor   

          at really high doses, sigma receptor overwhelmed 

Summary of CNS effects of morphine

1. analgesia

          analgesia, sedation, euphoria, mood change, mental cloudiness

2. respiration

          depression  

3. nausea and vomiting

          emetic, and antiemetic (main effect)   

4. cough reflex

          antitussive  

5. pupil size

          miosis (stimulation of cranial nerve 3)         

6. excitatory spinal reflexes

          stimulation produces convulsions (high doses)     

Cardiovascular effects of morphine lead to vasodilation

          morphine causes the release of histamine     

          suppression of central adrenergic tone         

          suppression of reflex vasoconstriction

Morphine effects on the vasculature

          morphine by itself has no direct effect on heart since no OPIOID receptor on heart, but indirectly it causes vasodilation lowering blood pressure         

          orthostatic hypotension from lying to sitting position test due to suppression of vasoconstriction reflex         

          due to less sensitivity of pCO2 in CNS, cerebral artery also dilates and have increased intracranial pressure

Morphine effects on the gastrointestinal system

          increase in tone and decrease in mobility leading to constipation        

          decreased concentration of HCl secretion    

          increased tone in stomach, small intestine, and large intestin

 

Reason for constipation produced by morphine

delay of passage of food (gastric contents) so more reabsorption of water

**tolerance does not develop (i.e. same amount of effect each time) to this constipation effect

Morphine    increases tone of smooth muscle

Morphine effects on various smooth muscles

biliary tract

          marked increase in the pressure in the biliary tract 

          10 fold increase over normal (normal is 20 mm h20 pressure) 

          increase due to contraction of sphincter of oddi    

urinary bladder

          tone of detrusor muscle increased      

          feel urinary urgency       

          have urinary retention due to increased muscle tone where sphincter closed off   

bronchial muscle

          bronchoconstriction can result 

          **contraindicated in asthmatics, particularly before surgery      

uterus

         

contraction of uterus can prolong labor       

Morphine

          due of increased muscle tone, it gives biliary tract pain that resembles biliary colic

Tolerance to morphine (therefore, must increase dose)

          nausea        

          analgesia     

          sedation      

          respiratory depression    

          cardiovascular      

          euphoric

not to:

          miosis         

          constipation

OVERVIEW OF THE EFFECTS OF MORPHINE

Toxicity of morphine

acute overdose

          respiratory depression    

          pinpoint pupils (miosis) 

          coma 

Treatment

1. establish adequate ventilation

2. give OPIOID antagonist (naloxone)

Naloxone

          it has no agonist activity 

          it displaces morphine from all receptors, reverses all of the effects of morphine    

          its effects are immediate (3-5 min)     

          duration is 30-45 minutes so have to reinject it

Heroin

          its effects can last 3-5 hours     

Therapeutic uses of morphine

          relief of pain         

          terminal illness     

          preoperative medications

          postoperative medications        

          acute pulmonary edema 

          constipating effect

          cough         

          obstetrical analgesia

Morphine for relief of pain don’t give morphine for severe head injuries since it dilates cerebral blood vessels causing an increase in intracranial pressure

Morphine for terminal illness used for the pain relief only , no effect to cure person, but makes their life tolerable with morphine

Morphine for preoperative medication morphine alleviates some of that pain use morphine, papaverine, fentanyl (generic name)

Fentanyl

          lasts 30 minutes    

          short duration       

          quick onset 

OPIOID give smooth induction into anesthesia

          pain relieving       

          reduces restlessness and anxiousness 

          reduces cough reflex      

          decreases pain      

          allows us to reduce amount of general anesthetic necessary

 

Disadvantage of using morphine in preoperative medications

          prolongs awakening time         

          spasms in smooth muscle         

          wheezing in asthmatic patients 

          nausea and vomiting can occur

          constipation and urinary retention      

          hypotension due to vasodilation        

          respiratory depression    

Morphine for postoperative medication

          controls pain and discomfort after surgery  

          lets person breathe deeply        

Disadvantage of using morphine in postoperative medications

          GI effect     

          constipation

          urinary retention   

          cough         

          cough good for clearing bronchial tree, but morphine reduces coughing         

Morphine for acute pulmonary edema with left sided heart failure

          related to anxiety level   

          high anxiety

          not breathing well

          pooling effect in heart    

          morphine relieves anxiety        

          breathing more deeply and pulmonary edema relieved    

Morphine for severe dysentery (ie. shigella)

          due to morphine’s constipation effect 

Codeine

          drug of choice for cough

          morphine would be too strong of a medication     

Morphine for obstetrical analgesia

          not used much since morphine crosses placental barrier  

          baby born with respiratory depression         

          meperidine is drug of choice for obstetrical analgesia     

Contraindications of morphine

          biliary colic

          due to increased pressure in biliary tract      

          acute head injuries

          due to increased intracranial pressure 

          asthmatics

Drug interactions with OPIOIDS

**in general, the coadministration of CNS depressants with OPIOID often produces at least an additive depression (potentiation)

OPIOID and phenothiazines

          produces an additive CNS depression as well as enhancement of the actions of OPIOID (respiratory depression)

          this combination may also produce a greater incidence of orthostatic hypotension

OPIOID and tricyclics antidepressants

          can produce increased hypotension   

          meperidine and MOA inhibitors        

          results in severe and immediate reactions that include excitation, rigidity, hypertension, and severe respiratory depression    

OPIOID and barbiturates

          increased clearance         

morphine and amphetamine

          enhanced analgesic effect

Morphine

at 3 hydroxyl and 6 hydroxyl positions have changes that change the potency and pharmacokinetics

Codeine

          change in the methyl group on 3 position (substituted for the hydroxyl group)

          one tenth the potency (analgesic properties) of morphine

          absorbed readily from GI tract 

          the absorption is more regular than morphine and more predictable   

          given orally

          metabolized like morphine through glucuronic acid        

          physical dependence is necessity of drug so you don’t go through withdrawal  tolerance and physical dependence is protracted from morphine since potency of codeine is low

          withdrawal from codeine is mild in relation to morphine

          antitussive drug for cough

Heroin (diacetylmorphine)

          at 3 and 6 hydroxy positions, there are acetyl groups instead of hydroxyl groups        

          it is anywhere from 3 to 4 times the analgesic potency of morphine   

          heroin is the most lipophilic of all the OPIOID     

          morphine is the least lipophilic of all the OPIOID

when heroin is ingested, it crosses the blood brain barrier rapidly (morphine crosses slow) where it is hydrolyzed to monoacetyl morphine (acetyl group got cleaved off) and then it is hydrolyzed to morphine making more of the drug in the brain making it 3 to 4 times more potent

          withdrawal symptoms of heroin similar to morphine, but more intense         

          mydriasis    

          diarrhea      

          vasoconstriction   

          dysphoria   

          etc.    

OPIOID withdrawal is NOT fatal , person won’t die; but with barbiturates, withdrawal can be fatal

withdrawal from OPIOID is called going cold turkey (goose bumps on skin) and also called kicking the habit due to leg motions

as a general rule, a drug that is more potent as analgesic than morphine will have more intense drug withdrawal symptoms

Hydromorphone (trade name is dilaudid)

          have ketone at 6 hydroxyl position of morphine   

          also strong agonist

          9 times more potent than morphine    

          more sedation than morphine so less euphoric feeling so not abused much

          less constipation   

          does not produce miosis 

          tolerance and physical dependence is more intense than morphine because of its high potency      

          respiratory depression same as morphine

Fentanyl (sublimaze, china white)

          synthetic drug      

          different structure than morphine       

          80 to 100 times more potent than morphine

          rapidly acting drug         

          used as preoperative medication        

          short acting (30-45 min)

          onset of action is 5 minutes      

          high potency        

          highly abused ,known as china white as street name

Meperidine

          produced in 1940’s

          wanted drug with less addictive liability than morphine, but it has same addictive liability as morphine 

          same CNS actions as morphine

          sedation, analgesia, respiratory depression  

          potency same as morphine       

unlike morphine:

          more respiratory depression     

          more bronchoconstriction activity      

          less constipation   

          no antitussive activity     

          **it causes mydriasis (not miosis)      

          toxic effects similar to atropine

          dry as a bone, blind as a bat, red as a beet, mad as a hatter        

          have dry mouth    

          drug absorbed orally      

          drug most abused by health care professionals due to its availability  

          withdrawal similar to morphine

 Non-narcotic Analgetics

The exact mechanism of action of paracetamol is uncertain, but it appears to be acting centrally. Aspirin and the NSAIDs inhibit cyclooxygenase, leading to a decrease in prostaglandin production; this reduces pain and also inflammation (in contrast to paracetamol and the opioids). Paracetamol has few side effects, but dosing is limited by possible hepatotoxicity (potential for liver damage). NSAIDs may predispose to peptic ulcers, renal failure, allergic reactions, and hearing loss. They may also increase the risk of hemorrhage by affecting platelet function. The use of certain NSAIDs in children under 16 suffering from viral illness may contribute to Reye’s syndrome.

Paracetamol and NSAIDs

Paracetamol or acetaminophen, is a common analgesic and antipyretic drug that is used for the relief of fever, headaches, and other minor aches and pains. Paracetamol is also useful in managing more severe pain, allowing lower dosages of additional non-steroidal anti-inflammatory drugs (NSAIDs) or opioid analgesics to be used, thereby minimizing overall side-effects. It is a major ingredient iumerous cold and flu medications, as well as many prescription analgesics. It is considered safe for human use in recommended doses, but because of its wide availability, deliberate or accidental overdoses are fairly common. In ancient and medieval times, known antipyretic agents were compounds contained in white willow bark (a family of chemicals known as salicins, which led to the development of aspirin), and compounds contained in cinchona bark.

 

Cinchona bark was also used to create the anti-malaria drug quinine. Quinine itself also has antipyretic effects. Efforts to refine and isolate salicin and salicylic acid took place throughout the middle- and late-19th century, and was accomplished by Bayer chemist Felix Hoffmann (this was also done by French chemist Charles Frédéric Gerhardt 40 years earlier, but he abandoned the work after deciding it was too impractical).When the cinchona tree became scarce in the 1880s, people began to look for alternatives. Two alternative antipyretic agents were developed in the 1880s: acetanilide in 1886 and phenacetin in 1887. Harmon Northrop Morse first synthesized paracetamol via the reduction of p-nitrophenol with tin in glacial acetic acid in 1878, however, paracetamol was not used medically for another 15 years. In 1893, paracetamol was discovered in the urine of individuals who had taken phenacetin, and was concentrated into a white, crystalline compound with a bitter taste. In 1899, paracetamol was found to be a metabolite of acetanilide. This discovery was largely ignored at the time. Paracetamol has long been suspected of having a similar mechanism of action to aspirin because of the similarity in structure. That is, it has been assumed that paracetamol acts by reducing production of prostaglandins, which are involved in the pain and fever processes, by inhibiting the cyclooxygenase (COX) enzyme as aspirin does. However, there are important differences between the effects of aspirin and those of paracetamol. Prostaglandins participate in the inflammatory response which is why aspirin has been known to trigger symptoms in asthmatics, but paracetamol has no appreciable anti-inflammatory action and hence does not have this side-effect. Furthermore, the COX enzyme also produces thromboxanes, which aid in blood clotting — aspirin reduces blood clotting, but paracetamol does not. Finally, aspirin and the other NSAIDs commonly have detrimental effects on the stomach lining, where prostaglandins serve a protective role, but, in recommended doses, paracetamol does not. Indeed, while aspirin acts as an irreversible inhibitor of COX and directly blocks the enzyme’s active site, paracetamol indirectly blocks COX, and this blockade is ineffective in the presence of peroxides. This might explain why paracetamol is effective in the central nervous system and in endothelial cells but not in platelets and immune cells which have high levels of peroxides.

In 2002 it was reported that paracetamol selectively blocks a variant of the COX enzyme that was different from the then known variants COX-1 and COX-2. This isoenzyme, which is only expressed in the brain and the spinal cord, is now referred to as COX-3. Its exact mechanism of action is still poorly understood, but future research may provide further insight into how it works. A single study has shown that administration of paracetamol increases the bioavailability of serotonin (5-HT) in rats, but the mechanism is unknown and untested in humans. In 2006, it was shown that paracetamol is converted to N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. As such, it activates the CB1 cannabinoid receptor; a CB(1) receptor antagonist completely blocks the analgesic action of paracetamol. Paracetamol is metabolized primarily in the liver, where most of it (60–90% of a therapeutic dose) is converted to inactive compounds by conjugation with sulfate and glucuronide, and then excreted by the kidneys. Only a small portion (5–10% of a therapeutic dose) is metabolized via the hepatic cytochrome P450 enzyme system (specifically CYP2E1); the toxic effects of paracetamol are due to a minor alkylating metabolite (N-acetyl-p-benzo-quinone imine, abbreviated as NAPQI) that is produced through this enzyme, not paracetamol itself or any of the major metabolites. The metabolism of paracetamol is an excellent example of toxication, because the metabolite NAPQI is primarily responsible for toxicity rather than paracetamol itself. At usual doses, the toxic metabolite NAPQI is quickly detoxified by combining irreversibly with the sulfhydryl groups of glutathione to produce a non-toxic conjugate that is eventually excreted by the kidneys. Paracetamol is contained in many preparations (both over-the-counter and prescription-only medications). In some animals, for example cats, small doses are toxic. Because of the wide availability of paracetamol there is a large potential for overdose and toxicity.^[9] Without timely treatment, paracetamol overdose can lead to liver failure and death within days. It is sometimes used in suicide attempts by those unaware of the prolonged timecourse and high morbidity (likelihood of significant illness) associated with paracetamol-induced toxicity in survivors. The toxic dose of paracetamol is highly variable. In adults, single doses above 10 grams or 150 mg/kg have a reasonable likelihood of causing toxicity. Toxicity can also occur when multiple smaller doses within 24 hours exceeds these levels, or even with chronic ingestion of doses as low as 4 g/day, and death with as little as 6 g/day. In children acute doses above 200 mg/kg could potentially cause toxicity. This higher threshold is largely due to children having relatively larger kidneys and livers than adults and hence being more tolerant of paracetamol overdose than adults. Acute paracetamol overdose in children rarely causes illness or death with chronic supratherapeutic doses being the major cause of toxicity in children. Since paracetamol is often included in combination with other drugs, it is important to include all sources of paracetamol when checking a person’s dose for toxicity. In addition to being sold by itself, paracetamol may be included in the formulations of various analgesics and cold/flu remedies as a way to increase the pain-relieving properties of the medication and sometimes in combination with opioids such as hydrocodone to deter people from using it recreationally or becoming addicted to the opioid substance, as at higher doses than intended the paracetamol will cause irreversible damage to the liver. To prevent overdoses, one should read medication labels carefully for the presence of paracetamol and check with a pharmacist before using over-the-counter medications.

Aspirin, or acetylsalicylic acid is a drug in the family of salicylates, often used as an analgesic (to relieve minor aches and pains), antipyretic (to reduce fever), and as an anti-inflammatory. It also has an antiplatelet (“blood-thinning”) effect and is used in long-term, low doses to prevent heart attacks and cancer.

Low-dose, long-term aspirin use irreversibly blocks the formation of thromboxane A₂ in platelets, producing an inhibitory effect on platelet aggregation. This anticoagulant property makes it useful for reducing the incidence of heart attacks. Aspirin produced for this purpose often comes in 75 or 81 mg, dispersible tablets and is sometimes called “junior aspirin” or “baby aspirin.” New evidence suggests that baby aspirin may not be as effective in preventing heart attacks and cerebrovascular accidents as previously thought. High doses of aspirin are also given immediately after an acute heart attack. These doses may also inhibit the synthesis of prothrombin and may, therefore, produce a second and different anticoagulant effect, but this is not well understood.

Its primary, undesirable side-effects, especially in higher doses, are gastrointestinal distress (including ulcers and stomach bleeding) and tinnitus. Another side-effect, due to its anticoagulant properties, is increased bleeding in menstruating women. Because there appears to be a connection between aspirin and Reye’s syndrome, aspirin is no longer used to control flu-like symptoms or the symptoms of chickenpox in minors. Aspirin was the first-discovered member of the class of drugs known as non-steroidal, anti-inflammatory drugs (NSAIDs), not all of which are salicylates, though they all have similar effects and a similar action mechanism.

Aspirin, as with many older drugs, has proven to be useful in many conditions. Despite its well-known toxicity it is widely used, since physicians are familiar with its properties. Indications for its use include:

• Fever

• Pain (especially useful for some forms of arthritis, osteoid osteoma, and chronic pain)

• Migraine

• Rheumatic fever (drug of choice)

• Kawasaki disease (along with IVIG)

• Pericarditis

• Coronary artery disease

• Acute myocardial infarction

In addition, aspirin is recommended (low dose, 75-81 mg daily) for the prevention of:

• Myocardial infarction — in patients with either documented coronary artery disease or at elevated risk of cardiovascular disease

• Stroke — as secondary prevention (i.e. to prevent recurrence)

For adults doses of 300 to 1000 mg are generally taken four times a day for fever or arthritis, with a maximum dose of 8000 mg a day. The correct dose of aspirin depends on the disease process that is being treated. For instance, for the treatment of rheumatic fever, doses near the maximal daily dose have been used historically. For the prevention of myocardial infarction in someone with documented or suspected coronary artery disease, doses as low as 75 mg daily (or possibly even lower) are sufficient. For those under 12 years of age, the dose previously varied with the age, but aspirin is no longer routinely used in children due to the association with Reye’s syndrome; paracetamol or other NSAIDs, such as Ibuprofen, are now being used instead. Kawasaki disease remains one of the few indications for aspirin use in children with aspirin initially started at 7.5-12.5 mg/kg body weight taken four times a day for up to two weeks and then continued at 5 mg/kg once daily for a further six to eight weeks.

• Aspirin should be avoided by those known to be allergic to ibuprofen or naproxen.

• Caution should be exercised in those with asthma or NSAID-precipitated bronchospasm.

• It is generally recommended that one seek medical help if symptoms do not improve after a few days of therapy.

• Caution should be taken in patients with kidney disease, peptic ulcers, mild diabetes, gout or gastritis; manufacturers recommend talking to one’s doctor before using this medicine.

• Taking aspirin with alcohol increases the chance of gastrointestinal hemorrhage (stomach bleeding).

• Children, including teenagers, are discouraged from using aspirin in cold or flu symptoms as this has been linked with Reye’s syndrome.

• Patients with hemophilia or other bleeding tendencies should not take salicylates.

• Some sources recommend that patients with hyperthyroidism avoid aspirin because it elevates T4 levels.

Common side-effects

• Gastrointestinal complaints (stomach upset, dyspepsia, heartburn, small blood loss). To help avoid these problems, it is recommended that aspirin be taken at or after meals. Undetected blood loss may lead to hypochromic anemia.

• Severe gastrointestinal complaints (gross bleeding and/or ulceration), requiring discontinuation and immediate treatment. Patients receiving high doses and/or long-term treatment should receive gastric protection with high-dosed antacids, ranitidine or omeprazole.

• Frequently, central effects (dizziness, tinnitus, hearing loss, vertigo, centrally mediated vision disturbances, and headaches). The higher the daily dose is, the more likely it is that central nervous system side-effects will occur.

• Sweating, seen with high doses, independent from antipyretic action

• Long-term treatment with high doses (arthritis and rheumatic fever): often increased liver enzymes without symptoms, rarely reversible liver damage. The potentially fatal Reye’s syndrome may occur, if given to pediatric patients with fever and other signs of infections. The syndrome is due to fatty degeneration of liver cells. Up to 30 percent of those afflicted will eventually die. Prompt hospital treatment may be life-saving.

• Chronic nephritis with long-term use, usually if used in combination with certain other painkillers. This condition may lead to chronic renal failure.

• Prolonged and more severe bleeding after operations and post-traumatic for up to 10 days after the last aspirin dose. If one wishes to counteract the bleeding tendency, fresh thrombocyte concentrate will usually work.

• Skin reactions, angioedema, and bronchospasm have all been seen infrequently.

• Patients that have the genetic disease known as Glucose-6-Phosphate Dehydrogenase deficiency (G6PD) should avoid this drug as it is known to cause hemolytic anemia in large doses depending on the severity of the disease.

The toxic dose of aspirin is generally considered greater than 150 mg per kg of body mass. Moderate toxicity occurs at doses up to 300 mg/kg, severe toxicity occurs between 300 to 500 mg/kg, and a potentially lethal dose is greater than 500 mg/kg.^[13] This is the equivalent of many dozens of the common 325 mg tablets, depending on body weight. Note that children cannot tolerate as much aspirin per unit body weight as adults can, even when aspirin is indicated. Label-directions should be followed carefully. COX-2 selective inhibitor is a form of Non-steroidal anti-inflammatory drug (NSAID) that directly targets COX-2, an enzyme responsible for inflammation and pain.

Selectivity for COX-2 reduces the risk of peptic ulceration, and is the main feature of celecoxib, rofecoxib and other members of this drug class. Cox-2-selectivity does not seem to affect other adverse-effects of NSAIDs (most notably an increased risk of renal failure), and some results have aroused the suspicion that there might be an increase in the risk for heart attack, thrombosis and stroke by a relative increase in thromboxane. Rofecoxib was taken off the market in 2004 because of these concerns. In the course of the search for a specific inhibitor of the negative effects of prostaglandins which spared the positive effects, it was discovered that prostaglandins could indeed be separated into two general classes which could loosely be regarded as “good prostaglandins” and “bad prostaglandins”, according to the structure of a particular enzyme involved in their synthesis, cyclooxygenase. Prostaglandins whose synthesis involves the cyclooxygenase-I enzyme, or COX-1, are responsible for maintenance and protection of the gastrointestinal tract, while prostaglandins whose synthesis involves the cyclooxygenase-II enzyme, or COX-2, are responsible for inflammation and pain. The existing nonsteroidal antiinflammatory drugs (NSAIDs) differ in their relative specificities for COX-2 and COX-1; while aspirin is equipotent at inhibiting COX-2 and COX-1 enzymes in vitro and ibuprofen demonstrates a sevenfold greater inhibition of COX-1, other NSAIDs appear to have partial COX-2 specificity, particularly meloxicam (Mobic). Studies of meloxicam 7.5 mg per day for 23 days find a level of gastric injury similar to that of a placebo, and for meloxicam 15 mg per day a level of injury lower than that of other NSAIDs; however, in clinical practice meloxicam can still cause some ulcer complications. A search for COX-2-specific inhibitors resulted in promising candidates such as valdecoxib, celecoxib, and rofecoxib, marketed under the brand names Bextra, Celebrex, and Vioxx respectively.

Combinations

Analgesics are frequently used in combination, such as the paracetamol and codeine preparations found in many non-prescription pain relievers. They can also be found in combination with vasoconstrictor drugs such as pseudoephedrine for sinus-related preparations, or with antihistamine drugs for allergy sufferers. The use of paracetamol, as well as aspirin, ibuprofen, naproxen, and other NSAIDS concurrently with weak to mid-range opiates (up to about the hydrocodone level) has been shown to have beneficial synergistic effects by combating pain at multiple sites of action–NSAIDs reduce inflammation which, in some cases, is the cause of the pain itself while opiates dull the perception of pain–thus, in cases of mild to moderate pain caused in part by inflammation, it is generally recommended that the two are prescribed together.

Topical or systemic

Topical analgesia is generally recommended to avoid systemic side-effects. Painful joints, for example, may be treated with an ibuprofen– or diclofenac-containing gel; capsaicin also is used topically. Lidocaine and steroids may be injected into painful joints for longer-term pain relief. Lidocaine is also used for painful mouth sores and to numb areas for dental work and minor medical procedures.

 

http://www.apchute.com/moa.htm

·                  physical dependence      

·                  euphoria     

·                  analgesia (supraspinal)   

·                  respiratory depression    

·        kappa

·                  sedation      

·                  analgesia (spinal)  

·                  miosis         

·        delta

·                 

analgesia (spinal & supraspinal)        

·                  release of growth hormone      

·        sigma

·                  dysphoria (opposite of euphoria)       

·                  hallucination         

·                  respiratory and vasomotor stimulation         

·                  mydriasis

·        OPIOID receptors in CNS, their distribution is not uniform they are at areas concerned with pain receptor locations beginning with highest concentration areas

·        1. cerebral cortex

·        2. amygdala

·        3. septum

·        4. thalamus

·        5. hypothalamus

·        6. midbrain

·        7. spinal cord

·        Sigma receptor also known as the “pcp receptor” since pcp will bind there  

·        Mu receptor high in areas of pain perception and at medulla (area for respiration)

 

Amino acid sequence of OPIOID peptides

·        In early 1950’s, it was thought that since morphine from poppy plant had relieved pain then it was likely that their was an endogenous substance for pain relief first found the receptor and then found the peptide which are enkephalins

·        Enkephalins

·                 

they are 5 amino acids long     

·                  also have met enkephalin (methionine at 5′ position) and leu enkephalin (leucine at 5′ position        enkephalins are neuromodulators since they are small peptides, it was found that they came from larger peptides (pro enkephalins)  proenkephalin gene codes for peptide 276 amino acid in length cleavage of proenkephalin gives 4 to 5 pieces of activated enkephalins

·                  Runners high enkephalins let a runner not feel the knee pains caused by running

·        Endorphin  30 amino acid peptide    

·                  last 5 amino acids are the same sequence as enkephalins 

·                  endorphins are neurohormones

·                  conservation between species   

·                  little difference in humans

·        Proopomelanocortin

·                 

various proteins that can come from this gene       

·                  gamma MSH, ACTH, beta LPH, alpha MSH, beta MSH, met Enk

·        Pharmacokinetics

·        absorption

·                  readily absorbed from GI tract, nasal mucosa, lung subcutaneous, intramuscular, and intravenous route 

·                  distribution 

·                  bound free morphine accumulates in kidney, lung, liver, and spleen         

·                  CNS is primary site of action (sedation)      

·        metabolism/excretion

·                  metabolic transformation in liver       

·                  conjugation with glucuronic acid       

·                  excreted by kidney         

·                  half life is 2.5 to 3 hours (does not persist in body tissue)         

·                  morphine 3 glucuronide in main excretion product         

·                  lose 90% in first day      

·                  duration of 10 mg dose is 3 to 5 hours        

·        Morphine administration

·                  oral morphine not given due to erratic oral availability    

·                  significant variable first pass effect from person to person and have intraspecies effect (same dose will vary in person day to day)  

·                  IV morphine acts promptly and its main effect is at the CNS

·        CNS is primary site of action of morphine

·                  analgesia     

·                  sedation      

·                  euphoria     

·                  mood change        

·                  mental cloudiness

·                  Morphine strongest analgesic today as a natural substance

·        Morphine analgesia

·                  changes our reaction and our perception of pain   

·        i.e. if person steps on your foot, still perceive somebody stepped on foot, but have lesser of a sensation where paiot blocked, but your reaction changes where your pain threshold has increased (i.e. can tolerate pain more)

·                  severe cancer pain is tolerated more when person is given morphine    

·                  relieves all types of pain, but most effective against continuous dull aching pain 

·                  sharp, stabbing, shooting pain also relieved by morphine

·                  Morphine sedation

·                  morphine causes sedation effect, but no loss of consciousness  

·                  person easily go asleep, but easily aroused unlike when on barbiturates where person goes into coma

·                  Morphine euphoria

·                  sense of well being         

·                  reason why morphine is abused

·         

·                  Morphine given to a pain free individual

·                  first experience is dysphoria    

·                  not experienced in person in pain

·        Initial Injection of opioid makes person sick, have anxiety, apathetic, lethargic, inability to concentrate, nausea, vomiting, and drowsiness  Morphine mood change person who is lively will become dull when using morphine

·        Morphine mental cloudiness difficulty in concentration and have apathy

·        Effects of morphine on respiration there is a primary and continuous depression of respiration related to dose decrease rate decrease volume          decrease tidal exchange  mu receptor activation produces respiratory depression; with increase in dose, further respiratory depression Morphine  CNS becomes less responsive to pCO2 thereby causing a build up of CO2

·        Depression on medulla affect brain center on rhythm and responsiveness gives irregular breathing patterns. As increase dose, one will see periods of apnea Respiratory centers less responsive to pCO2 as well as medullary centers for responsiveness to CO2 in blood so irregular breathing (short breath) normal response 2 to 3 hours after normal dose Morphine initially stimulates chemoreceptor trigger zone (CTZ)and then it will depress CTZ (antiemetic effect) this may be one of the reasons for the dysphoria in pain free people

·        Morphine  nausea and vomiting

·                  morphine initially stimulates the CTZ -> emetic    

·                  later effect is antiemetic  

·        cough reflex

·                  antitussive effect due to direct depression of cough center in the medulla      

·        pupil size

·                  morphine produces miosis (pinpoint pupils)

·                  tolerance does not develop to miosis  

·        excitatory and spinal reflexes

·                  high doses of many OPIOID cause convulsions

·                 

Central trigger zone

·                  in postrema of medulla   

·                  stimulation by stretch receptors causes nausea and vomiting     

·                  has afferents from gut and ear  

·                  involved in motion sickness     

·        Codeine in cough syrup

·                  it has an antitussive effect        

·        Morphine and all OPIOID

·                  they cause miosis (pinpoint pupils)    

·                  kappa receptor effect      

·                  gives indication that patient has OPIOID overdose

·                  pinpoint pupils responsive to bright light    

·                  if block kappa receptor (causes miosis), see mydriasis from sigma effect

·                  oculomotor nerve (CN3) is stimulated by kappa receptor site   

·                  start at edenmeyeroff nucleus. see parasympathetic discharge at oculomotor nerve giving pin point pupils    

atropine only blocks effect indicating parasympathetics only partially explains the miosis

·        High doses (overdose situation) of morphine

·                  can cause convulsions    

·                  this is stimulation at sigma receptor   

·                  at really high doses, sigma receptor overwhelmed 

·        Summary of CNS effects of morphine

·        1. analgesia

·                  analgesia, sedation, euphoria, mood change, mental cloudiness

·        2. respiration

·                  depression  

·        3. nausea and vomiting

·                  emetic, and antiemetic (main effect)   

·        4. cough reflex

·                  antitussive  

·        5. pupil size

·                  miosis (stimulation of cranial nerve 3)         

·        6. excitatory spinal reflexes

·                  stimulation produces convulsions (high doses)     

·        Cardiovascular effects of morphine lead to vasodilation

·                  morphine causes the release of histamine     

·                  suppression of central adrenergic tone         

·                  suppression of reflex vasoconstriction

·        Morphine effects on the vasculature

·                  morphine by itself has no direct effect on heart since no OPIOID receptor on heart, but indirectly it causes vasodilation lowering blood pressure      

·                  orthostatic hypotension from lying to sitting position test due to suppression of vasoconstriction reflex          due to less sensitivity of pCO2 in CNS, cerebral artery also dilates and have increased intracranial pressure

·        Morphine effects on the gastrointestinal system

·                  increase in tone and decrease in mobility leading to constipation          

·                  decreased concentration of HCl secretion    

·                  increased tone in stomach, small intestine, and large intestin

·         Reason for constipation produced by morphine

·        delay of passage of food (gastric contents) so more reabsorption of water

·        **tolerance does not develop (i.e. same amount of effect each time) to this constipation effect

·        Morphine    increases tone of smooth muscle

·        Morphine effects on various smooth muscles

·        biliary tract

·                  marked increase in the pressure in the biliary tract 

·                  10 fold increase over normal (normal is 20 mm h20 pressure) 

·                  increase due to contraction of sphincter of oddi    

·        urinary bladder

·                  tone of detrusor muscle increased      

·                  feel urinary urgency       

·                  have urinary retention due to increased muscle tone where sphincter closed off        

·        bronchial muscle

·                  bronchoconstriction can result 

·                  **contraindicated in asthmatics, particularly before surgery      

·        uterus

·                 

contraction of uterus can prolong labor       

·        Morphine

·                  due of increased muscle tone, it gives biliary tract pain that resembles biliary colic    

·        Tolerance to morphine (therefore, must increase dose)

·                  nausea        

·                  analgesia     

·                  sedation      

·                  respiratory depression              

·                  cardiovascular      

·                  euphoric

·        not to:

·                  miosis         

·                  constipation

·        OVERVIEW OF THE EFFECTS OF MORPHINE

·        Toxicity of morphine

·        acute overdose

·                  respiratory depression    

·                  pinpoint pupils (miosis) 

·                  coma 

·        Treatment

·        1. establish adequate ventilation

·        2. give OPIOID antagonist (naloxone)

·        Naloxone

·                  it has no agonist activity 

·                  it displaces morphine from all receptors, reverses all of the effects of morphine         

·                  its effects are immediate (3-5 min)     

·                  duration is 30-45 minutes so have to reinject it

·        Heroin

·                  its effects can last 3-5 hours     

·        Therapeutic uses of morphine

·                  relief of pain         

·                  terminal illness     

·                  preoperative medications

·                  postoperative medications        

·                  acute pulmonary edema 

·                  constipating effect

·                  cough         

·                  obstetrical analgesia

·        Morphine for relief of pain don’t give morphine for severe head injuries since it dilates cerebral blood vessels causing an increase in intracranial pressure

·        Morphine for terminal illness used for the pain relief only , no effect to cure person, but makes their life tolerable with morphine

·        Morphine for preoperative medication morphine alleviates some of that pain use morphine, papaverine, fentanyl (generic name)

·        Fentanyl

·                  lasts 30 minutes    

·                  short duration       

·                  quick onset 

·        OPIOID give smooth induction into anesthesia

·                  pain relieving       

·                  reduces restlessness and anxiousness 

·                  reduces cough reflex      

·                  decreases pain      

·                  allows us to reduce amount of general anesthetic necessary

·         Disadvantage of using morphine in preoperative medications

·                  prolongs awakening time         

·                  spasms in smooth muscle         

·                  wheezing in asthmatic patients 

·                  nausea and vomiting can occur

·                  constipation and urinary retention      

·                  hypotension due to vasodilation        

·                  respiratory depression    

·        Morphine for postoperative medication

·                  controls pain and discomfort after surgery  

·                  lets person breathe deeply        

·        Disadvantage of using morphine in postoperative medications

·                  GI effect     

·                  constipation

·                  urinary retention   

·                  cough         

·                  cough good for clearing bronchial tree, but morphine reduces coughing    

·        Morphine for acute pulmonary edema with left sided heart failure

·                  related to anxiety level   

·                  high anxiety

·                  not breathing well

·                  pooling effect in heart    

·                  morphine relieves anxiety        

·                  breathing more deeply and pulmonary edema relieved    

·        Morphine for severe dysentery (ie. shigella)

·                  due to morphine’s constipation effect 

·        Codeine

·                  drug of choice for cough

·                  morphine would be too strong of a medication     

·        Morphine for obstetrical analgesia

·                  not used much since morphine crosses placental barrier  

·                  baby born with respiratory depression         

·                  meperidine is drug of choice for obstetrical analgesia     

·        Contraindications of morphine

·                  biliary colic

·                  due to increased pressure in biliary tract      

·                  acute head injuries

·                  due to increased intracranial pressure 

·                  asthmatics

·        Drug interactions with OPIOIDS

·        **in general, the coadministration of CNS depressants with OPIOID often produces at least an additive depression (potentiation)

·        OPIOID and phenothiazines

·                  produces an additive CNS depression as well as enhancement of the actions of OPIOID (respiratory depression)    

·                  this combination may also produce a greater incidence of orthostatic hypotension  

·        OPIOID and tricyclics antidepressants

·                  can produce increased hypotension   

·                  meperidine and MOA inhibitors        

·                  results in severe and immediate reactions that include excitation, rigidity, hypertension, and severe respiratory depression

·        OPIOID and barbiturates

·                  increased clearance         

·        morphine and amphetamine

·                  enhanced analgesic effect

·        Morphine

·        at 3 hydroxyl and 6 hydroxyl positions have changes that change the potency and pharmacokinetics

·        Codeine

·                  change in the methyl group on 3 position (substituted for the hydroxyl group)

·                  one tenth the potency (analgesic properties) of morphine

·                  absorbed readily from GI tract 

·                  the absorption is more regular than morphine and more predictable         

·                  given orally

·                  metabolized like morphine through glucuronic acid        

·                  physical dependence is necessity of drug so you don’t go through withdrawal  tolerance and physical dependence is protracted from morphine since potency of codeine is low   

·                  withdrawal from codeine is mild in relation to morphine

·                  antitussive drug for cough

·         Heroin (diacetylmorphine)

·                  at 3 and 6 hydroxy positions, there are acetyl groups instead of hydroxyl groups  

·                  it is anywhere from 3 to 4 times the analgesic potency of morphine         

·                  heroin is the most lipophilic of all the OPIOID     

·                  morphine is the least lipophilic of all the OPIOID

·        when heroin is ingested, it crosses the blood brain barrier rapidly (morphine crosses slow) where it is hydrolyzed to monoacetyl morphine (acetyl group got cleaved off) and then it is hydrolyzed to morphine making more of the drug in the brain making it 3 to 4 times more potent

·                  withdrawal symptoms of heroin similar to morphine, but more intense        

·                  mydriasis    

·                  diarrhea      

·                  vasoconstriction   

·                  dysphoria   

·                  etc.    

·        OPIOID withdrawal is NOT fatal , person won’t die; but with barbiturates, withdrawal can be fatal

·        withdrawal from OPIOID is called going cold turkey (goose bumps on skin) and also called kicking the habit due to leg motions

·        as a general rule, a drug that is more potent as analgesic than morphine will have more intense drug withdrawal symptoms

·        Hydromorphone (trade name is dilaudid)

·                  have ketone at 6 hydroxyl position of morphine   

·                  also strong agonist

·                  9 times more potent than morphine    

·                  more sedation than morphine so less euphoric feeling so not abused much        

·                  less constipation   

·                  does not produce miosis 

·                  tolerance and physical dependence is more intense than morphine because of its high potency      

·                  respiratory depression same as morphine

·        Fentanyl (sublimaze, china white)

·                  synthetic drug      

·                  different structure than morphine       

·                  80 to 100 times more potent than morphine

·                  rapidly acting drug         

·                  used as preoperative medication        

·                  short acting (30-45 min)

·                  onset of action is 5 minutes      

·                  high potency        

·                  highly abused ,known as china white as street name

·        Meperidine

·                 

produced in 1940’s

·                  wanted drug with less addictive liability than morphine, but it has same addictive liability as morphine  

·                  same CNS actions as morphine

·                  sedation, analgesia, respiratory depression  

·                  potency same as morphine       

·        unlike morphine:

·                  more respiratory depression     

·                  more bronchoconstriction activity      

·                  less constipation   

·                  no antitussive activity     

·                  **it causes mydriasis (not miosis)      

·                  toxic effects similar to atropine

·                  dry as a bone, blind as a bat, red as a beet, mad as a hatter        

·                  have dry mouth    

·                  drug absorbed orally      

·                  drug most abused by health care professionals due to its availability         

·                  withdrawal similar to morphine

·        Diphenoxylate (lomotil)

·                  can be OTC drug now    

·                  therapeutic use is antidiarrhea drug (treats diarrhea)        

·                  meperidine type drug     

·                  has very little analgesic properties at therapeutic dose     

·                  no antitussive effect       

·                  at high doses it has analgesic problems        

·                  causes respiratory depression and euphoria at high doses

·        Methadone

·                  pharmacological activity similar to morphine        

·                  long duration of activity 

·                  absorbed well orally       

·                  lasts long time      

·                  16 to 20 hour duration of action        

·                  used in maintenance program for narcotic treatment

·        all OPIOID are cross tolerant to each other since all act on same receptor site

·        want to replace heroin from receptor site (short duration of action of 2 hours) with methadone (16 to 20 hour duration of action) to get people off of heroin while preventing withdrawal

·                  powerful pain reliever    

·                  same potency as morphine

·        Antagonism of Morphine

·        two drugs: naloxone and naltrexone (pure antagonist)

·        Naloxone

·                  no analgesic activity at all        

·                  competitive antagonist at mu, kappa, and sigma receptor

·                  displaces morphine and other OPIOID from receptor site         

·                  reverses all actions of the OPIOID and does it rather quickly   

·                  it will precipitate withdrawal    

·                  person on heroin, thealoxone will precipitate withdrawal, but naloxone effects are seen in the first five minutes and it only lasts for 30 minutes:     

·                  increased blood pressure

·                  diarrhea      

·                  reversible respiratory depression       

·                  metabolized same as morphine through glucuronic acid and excreted through kidney

·                  after naloxone, when person wakes up, person will be very irritable and agitated; after 30-45 minutes coma will return so  closely supervise patients;  give  another dose after drug wears off.

·                 

·        Naltrexone

·                  same effect of naloxone except it is used orally so can’t use it if for person with acute toxicity        

·                  long duration of activity 

·                  single dose block action of heroin effects for 24 hours   

·                  used for emergency treatment  

·                  once stabilized, give patient naltrexone        

·                  patient get no euphoric effect from heroin so person gets off heroin (negative reinforcement)

·                  approved for use by the FDA  

·                  also used for treatment of alcoholism

Opioids

Nomenclature:

“Narcotic” is a somewhat imprecise term because it suggests “narcosis”, which is indicated of a somnolent state or “sleepy” state.

“Opioid analgesic” and therefore is a more appropriate term emphasizing the clinically important analgesic property which is the pharmacological property of importance in the therapeutic application of these agents. 

Accordingly, opioids are used without the expectation that they themselves will cause sleep.  However, opioids are frequently used in combination with anesthetics and in that context anesthesia may be obtained requiring less anesthetic.

Opioids: Definition—

All natural/semisynthetic opium alkaloid derivatives, synthetic agents, and other agents whose opioid-like effects are  blocked by classical opioid antagonists, such as naloxone (Narcan) or naltrexone (ReVia).

Source:

Opium — from the opium poppy (Papaver somniferum).  Opium is obtained following drying the milky juice from unripe seed pod.

Opium has a characteristic odor and bitter-taste with its chief active ingredient being morphine. 

Also present are codeine, thebaine (a non-analgesic agent), noscapine and papaverine, a non-analgesic vasodilator.  

Tincture of opium is called laudanum. (Tincture is a generic term which refers to an alcohol solution of a nonvolatile medicine. Paregoric is a mixture of opium, alcohol, and camphor.)

Classification/Chemistry:

Opioid Classification:

An opioid full agonist activates opioid receptors, exhibiting high efficacy.  

High efficacy refers to a maximal opioid effect, typically pain relief.  

Full agonists may have comparable efficacies with the differing potencies meaning that different amounts of one drug compared to another may have to be given in order to achieve a maximal effect.

A partial agonist may itself cause agonist effects but because they can displace through competitive action a full agonist from its receptor, the net effect is a reduction in drug effect.  As a result, a partial agonist, depending on circumstance, can act as either in agonist or an antagonist.

Antagonists: Pharmacological effects of opioids are mediated by interaction with differing opioids receptor types.  

Most of the pharmacological effects as well as side effects, at least respiratory depression, are mediated by opioid-mu receptor interactions.  

These agonist-mediated effects may be blocked by competitive inhibition by agents that occupy the the same receptor by do not activate it, yet prevent activation by agonists.  

Furthermore, an opioid might be an agonist at one receptor subtype, but only a partial agonist or even in antagonist at another subtype.

Examples:

Naloxone (Narcan): pure antagonist: no effects normally associated with agonist binding

Morphine: full agonist at mu receptor

Codeine: partial or “weak” agonist — less than maximal theoretical effect despite complete receptor saturation

Nalbuphine (Nubain)  : agonist that one opioid receptor; antagonist at another

Chemical substitutions:

Partial agonist/antagonist characteristics: replacement of methyl moiety on the nitrogen atom with larger substituents:

Allyl substitution– nalorphine and naloxone

Substitutions at the C3 and C6 morphine hydroxyl groups (see below)

Pharmacokinetic properties altered

Methyl substitution at C3  reduces first-pass hepatic metabolism by glucuronide conjugation: — as a consequence codeine and oxycodone have a higher oral: parenteral potency

 

Acetylation of both morphine hydroxyls = heroin {more rapid access across the blood-brain barrier compared morphine}; in the brain heroin is rapidly hydrolyzed to monoacetylmorphine and morphine

Endogenous Opioid Peptides: The rationale for endogenous opioid peptides came from the idea that opioid receptors are probably present in the body for the purpose of interacting with endogenous or naturally occurring substances.  As a consequence, research proceeded to attempt identification of these naturally occurring substances now known as  ß-endorphins and related peptides.

Morphine (and related agents) cause analgesia by acting at the brain regions containing peptides which have opioid-like properties

Endogenous substances = endogenous opioid peptides

Previous used term “endorphin” now refers to ß-endorphins and related peptides derived from the precursor: prepro-opiomelanocortin

Most widely distributed opioid analgesic peptides:

pentapeptides

methionine-enkephalin (met-enkephalin)

leucine-enkephalin (leu-enkephalin)

Three major precursor proteins:

Prepro-opiomelanocortin (POMC) {contains}:

met-enkephalin sequence

ß-endorphin sequence

some nonopioid peptides:

ACTH

ß-lipotropin

melanocyte-stimulating hormone

Preproenkephalin (proenkephalin A ) {contains}:

six copies of met-enkephalin

one copy of leu-enkephalin

Preprodynorphin (proenkephalin B) {contains– active peptides containing the leu-enkephalin sequence}:

dynorphin A

dynorphin B

a and ß neoendorphin

Endogenous opioid precursors which are localized at pain modulation brain regions are probably released during stress, including pain or pain anticipation.  

Also, precursor molecules for endogenous opioids are localized in adrenal medulla and gut neural plexuses

Pharmacokinetics

Absorption:

Opioid analgesics are generally well absorbed by cutaneous/intramuscular/mucosal surfaces

Transdermal fentanyl represents an important Route of Administration

Gastrointestinal absorption:

Some opioids– subject to first-pass effects:

Codeine; oxycodone — high oral: parenteral potency (protected from conjugation by substitution on C3 aromatic hydroxyl)

Distribution:

Various extent of plasma protein binding

Highest concentrations in tissues will be a  function of perfusion

Skeletal muscle represents the largest reservoir

For highly lipophilic opioids (e.g. fentanyl), there is significant concentration in adipose tissue

Blood Brain Barrier:

Amphoteric agents (possessing both an acidic and basic group, e.g. morphine {phenolic hydroxyl at C3}: greatest difficulty for brain entry

Other substitutions that C3 improve blood-brain barrier penetration: e.g., heroin, codeine

 Neonatal considerations: neonates lack the blood-brain barrier:

  Placental opioid transfer (uses in obstetric analgesia) can result in depressed respiration in the newborn.

Metabolism:

Conversion to polar metabolites; renal excretion

Opioids with hydroxyl groups are likely conjugated with glucuronic acid

Examples: morphine, levorphanol (Levo-dromoran) 

Morphine-6-glucuronide: analgesic potency (perhaps > parent compound morphine)

  In patients with compromised renal function, accumulation of metabolites occurs which prolongs  analgesia

Esters-type opioids are: hydrolyzed by tissue esterases:

Examples: heroin, remifentanil (short duration of action)

N-demethylation: minor pathway

Accumulation of demethylated meperidine (Demerol)  metabolite, normeperidine:

patients with decreased renal function or on high dosages: CNS excitatory effects:

  seizures (more likely in children)

Oxidative metabolism (hepatic) primary route of phenylpiperidine opioid metabolism:

fentanyl (Sublimaze)

alfentanil (Alfenta)

sufentanil (Sufenta)

Excretion:

Polar metabolites — renal; small amounts excreted unchanged

Glucuronide conjugates — bile (enterohepatic circulation minor)

Pharmacodynamics

Mechanism of Action:

Analgesia: specific receptor binding — localization:

spinal cord

brain

Receptor Types:

Mu (m)

Delta (d)

Kappa (k)

General Opioid Receptor Characteristics:

G protein coupled receptor family

Significant amino acid sequence homology

Each-receptor: subtypes

Mu1, Mu2

Delta1, Delta2

Kappa1, Kappa2

Receptor types and physiological effects:

Mu (m) :Analgesia, euphoria, respiratory depression, physiological dependence

Most opioid analgesics: act at the mu receptor

Delta (d) and Kappa (k): Spinal analgesia

Drugs/endogenous opioids: Receptor- type affinity

morphine — (m)

pentazocine — (k) some (m)

endogenous opioid peptides:

leu-enkephalin –(d)

dynorphin –(k)

Cellular Action:

Opioids: G protein linked-– affecting

Ion channel state

Intracellular Ca2+ levels

Protein phosphorylations states

Two well-defined opioid actions:

Reduce neurotransmitter release; by closing a voltage-gated Ca2+ channel on presynaptic neuronal terminals Or

Inhibit postsynaptic neurons (hyperpolarization) by increasing and K+ channel conductance

Spinal cord presynaptic sites:

Reduced transmitter released– affects acetylcholine, norepinephrine, glutamate, serotonin, substance P

Serotonin, bradykinin, histamine, prostaglandins, substance P (sP) , and various ions (ie, H+ or K+)–the biochemical mediators released as a result of tissue injury–have been implicated iociceptive activation and sensitization (hyperalgesia).

Hyperalgesia results in enhancement of spontaneous pain via a reduction in pain threshold and a lengthening in duration of nociceptor response to stimuli.

PGE1, PGE2, and PGF2a, are the most potent prostaglandins to produce these sensitization effects.

Substance P, synthesized by cells of the spinal ganglia, has been identified at the peripheral terminal of unmyelinated primary afferent fibers.

 This putative neurotransmitter may play a role in the propagation of visceral nociceptive pain from the gastrointestinal (GI) tract, ureters, and urinary bladder.

Opioid Receptor Distribution

Spinal cord: dorsal horn

Primary afferents to pain transmissioeurons

Opioid agonists:

Inhibit excitatory transmitters release from these primary afferents

Inhibit dorsal horn pain transmissioeurons

Clinical application: directed administration of opioid agonists allow regional analgesia which minimizes CNS side effects

Systemic Opioid Administration:

Action in both supraspinal and spinal sites

Important opioid binding sites in descending pathways

Rostral ventral medulla

Locus ceruleus (see below)

Midbrain periaqueductal gray

 

Administration of exogenous opioids promotes release of endogenous opioids

Reticular formation (RF), vestibular nuclei (V), cerebellar roof nuclei (R), periaquiductal gray (PG).  Posterior hypothalamic nuclei (P), paraventricular hypothalamic nucleus (PV), substantia nigra (SN),  Thalamic nuclei (T), preoptic hypothalamic nuclei (PO), locus ceruleus (LC), median raphe nuclei (MR) . 

Tolerance/Physical Dependence

Repeated opioid administration results in a gradual loss of effect, e.g. tolerance

Physical Dependence = physiological withdrawal symptoms (abstinence syndrome) if an antagonist is administered or the agonist is stopped.

Tolerance is not developed equally to all opioid effects.

 

Abuse of Opioids:

 

 

 

Antitussives

Codeine Dextromethorphan Delsym

 

 

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