Pharmacology: Opioid Analgesics
Terms in this set (81)
Which opioid receptors mediate supraspinal analgesia?
Supraspinal analgesia is mediated by opioid receptors µ,κ and δ .
Which opioid receptors mediate spinal analgesia?
Spinal analgesia is mediated by opioid receptors µ,κ and δ .
Which opioid receptors mediate respiratory depression?
Respiratory depression is mediated by the µ opioid receptor .
Which opioid receptor mediate reduced GI motility?
Reduced GI motility is mediated by opioid receptors µ and δ .
Which opioid receptor mediate psychotomimesis
Psychotomimesis is mediated by the κ opioid receptor.
Which opioid receptor mediates sedation?
Sedation is mediated by the µ and κ opioid receptors.
What are the two main actions of opioid drugs on neurons?
The opioids have two well-established actions on neurons:
1. They close voltage-gated Ca2+ channels on presynaptic nerve terminals and thereby reduce neurotransmitter release.
2. They open K+ channels thus hyperpolarizing and inhibiting postsynaptic neurons.
Both actions can reduce the release of a large number of neurotransmitters, including glutamate (the main excitatory neurotransmitter released from nociceptive nerve terminals), acetylcholine, norepinephrine, serotonin and substance P.
How do opioid drugs mediate spinal analgesia ?
inhibit release of excitatory neurotransmitters (substance P and glutamate) from these primary afferents
. Opioids also directly
inhibit the dorsal horn pain transmission neuron
. Thus, opioids exert a powerful analgesic effect directly on the spinal cord. This spinal action has been exploited by direct application of opioid agonists to the spinal cord, which provides regional analgesic effect while minimizing the unwanted respiratory depression, nausea and vomiting, and sedation that may occur from the supraspinal actions of systemically administered drugs.
How do opioid drugs mediate supraspinal analgesia?
Pain-inhibitory descending neurons send processes to the spinal cord and inhibit pain transmission neurons. Pain-inhibitory descending neurons are activated by opioids. This activation results from the inhibition of inhibitory neurons by
opioids. Under most circumstances opioids are given systemically and so act concurrently at both spinal and supraspinal sites, and interaction at these sites tends to increase their overall analgesic efficacy.
How do opioid drugs mediate peripheral analgesia?
There are opioid µ receptors on the peripheral terminals of sensory neurons. Stimulation of peripheral µ receptors by opioids decreases sensory neuron activity and transmitter release. Peripheral administration of opioids, e.g., into the knees of patients undergoing arthroscopic knee surgery, has shown some clinical benefit.
What are the classifications of opioid drugs?
This group includes most of the typical morphine-like drugs. They all have high affinity for µ receptors and generally lower affinity for δ and κ receptors.
and mixed agonist-antagonists. These drugs combine a degree of agonist and antagonist activity on different receptors.
The most important examples are naloxone and naltrexone.
What are the CNS effects of opioid drugs?
Sedation and drowsiness
Nausea and vomiting
Why is sedation an important side effect of opioids?
Sedation is a frequent effect of opioid action. It places ambulatory patients at risk for accidents.
How do opioid drugs mediate respiratory depression?
Opioid analgesics can evoke respiratory depression by reducing responsiveness of the brainstem respiratory centers to CO2. The respiratory depression is generally not a serious clinical problem.
How do opioid drugs cause cough suppression?
Opioids depress the cough reflex at least in part by a direct effect on a cough center in the medulla. There is no obligatory relationship between depression of respiration and depression of coughing and effective antitussive agents are available that do not depress respiration
How do opioid drugs cause miosis?
Morphine and most µ and κ agonists cause miosis of the pupil by an excitatory action on the parasympathetic nerve innervating the pupil. Following toxic doses of µ agonists, the miosis is marked and pinpoint pupils are pathognomonic. Some tolerance to the miotic effect develops, but addicts with high circulating concentrations of opioids continue to have constricted pupils. During severe respiratory depression and asphyxia, miosis may revert to mydriasis.
What are the peripheral effects of opioid drugs?
Opioids contract biliary smooth muscle, which may result in
Renal function is depressed
due to decreased renal plasma
May prolong labour
. Mechanism unclear, but both peripheral and central effects can reduce tone.
Opioid analgesics stimulate release of *ADH, PRL, and
somatotropin but inhibit release of LH*.
How do opioid drugs cause hypotension?
Opioids inhibit the vasomotor centre in the brainstem causing
peripheral vasodilation; they also inhibit compensatory baroreflexes and increase histamine release.
How do opioid drugs cause constipation?
Opioid receptors exist in gastrointestinal tract, and constipating effects are mediated through an action on the local enteric nervous system, as well as in the CNS.
How are opioids in general metabolized and excreted?
Opioids are converted in large part to polar metabolites (mostly glucuronides), which are then excreted by the kidneys. In addition, glucuronide conjugates are found in the bile, but enterohepatic circulation represents only a small portion of the excretory process.
To which compounds are morphine metabolized and when are their effects significant?
Morphine is primarily conjugated to morphine-3-glucuronide (M3G), a compound with neuroexcitatory properties. The neuroexcitatory effects of M3G are not mediated by opioid receptors. Approximately 10% of morphine is metabolized to morphine-6-glucuronide (M6G), an active metabolite with analgesic potency 4-6 times that of its parent compound.
M3G and M6G are relatively polar metabolites with limited ability to cross the brain barrier, and probably do not contribute significantly to the usual CNS effects of morphine given acutely.
The effects of these active metabolites should be considered in patients with renal impairment.
How are esters such as heroin and remifentanil metabolized?
Esters such as heroin and remifentanil are rapidly hydrolyzed by common tissue esterases. Heroin (diacetylmorphine) is hydrolyzed to monoacetylmorphine and finally to morphine, which is then conjugated with glucuronic acid.
What is the metabolite of meperidine?
Accumulation of a metabolite of meperidine, normeperidine, may occur in patients with decreased renal function and in those receiving multiple high doses of the drug. In high concentrations, normeperidine may cause
How is fentanyl metabolized?
Fentanyl is metabolized by
in the liver. No active metabolites of fentanyl have been reported.
How are codeine, oxycodone and hydrocodone metabolized?
Codeine, oxycodone, and hydrocodone are metabolized in the liver by
, resulting in the production of metabolites of greater potency. For example,
codeine is demethylated to morphine
What are the clinical uses of opioid analgesics?
Acute Pulmonary Edema
How is morphine used to treat pulmonary edema?
IV morphine relieves dyspnea caused by pulmonary edema
associated with left ventricular failure. Proposed mechanisms include reduced anxiety, and reduced cardiac preload and afterload. If respiratory depression is a problem, furosemide may be preferred. On the other hand, morphine can be particularly useful when treating painful myocardial ischemia with pulmonary edema.
How are opioids used to treat shivering? Which is the best choice for this reason?
Although all opioid agonists may reduce shivering, meperidine has the most pronounced anti-shivering properties. Meperidine apparently blocks shivering by activating α2-adrenoceptors.
What are the uses of opioid drugs as analgesics?
• Opioids are frequently used as premedicant drugs before anesthesia and surgery because of their sedative, anxiolytic and analgesic properties.
• Opioids are also used intraoperatively both as adjuncts to other anesthetic agents and, in high doses, as a primary component of the anesthetic regimen, most commonly in cardiovascular surgery and other types of high-risk surgery where a primary goal is to minimize cardiovascular depression.
• Because of their direct action on the spinal cord, opioids can also be used as regional analgesics by administration into the epidural or subarachnoid spaces of the spinal
How are opioid drugs addictive?
With frequent administration there is gradual loss in effectiveness, ie tolerance. Physiological dependence develops too. This is defined as the occurrence of a withdrawal or abstinence syndrome when the drug is stopped or an antagonist is administered. The euphoria, indifference to stimuli, and sedation usually caused by opioid analgesics, especially when given IV, tend to promote their compulsive use. Physical dependence is common when opioids are used for therapeutic purposes. However, addiction is not.
Why is the use of a pure agonist with a weak partial agonist contraindicated?
The use of a pure agonist with a weak partial agonist is contraindicated because when a weak partial agonist such as pentazocine is given to a patient also receiving a full agonist (eg, morphine), there is a risk of diminishing analgesia or even inducing a state of withdrawal; combining full agonist with partial agonist opioids should be avoided.
Why is the use of opioids contraindicated in people with head injuries?
CO2 retention caused by respiratory depression results in cerebral vasodilation. In patients with elevated intracranial pressure, this may lead to lethal alterations in brain function.
Why is the use of opioids contraindicated in pregnant women?
In pregnant women who are chronically using opioids, the fetus may become physically dependent in utero and manifest withdrawal symptoms in the early postpartum period.
Why is the use of opioids contraindicated in patients with depressed pulmonary function?
In patients with borderline respiratory reserve, the depressant properties of the opioid analgesics may lead to acute respiratory failure.
Why is the use of opioids contraindicated in patients with impaired hepatic function?
Morphine and its congeners are metabolized primarily in the liver, therefore their use in patients in prehepatic coma may be questioned.
Why is the use of opioids contraindicated in patients with impaired renal function?
Half-life of opioids is prolonged in patients with impaired renal function. Morphine and its active glucuronide metabolite may accumulate.
Why is the use of opioids contraindicated in patients with endocrine disease?
Patients with adrenal insufficiency (Addison's disease) or hypothyroidism (myxedema) may have prolonged and exaggerated responses to opioids.
What classes of drugs have interactions with opioids?
: Increase CNS depression, particularly respiratory depression.
: Increase sedation. Variable effects on respiratory depression. Accentuation of CV effects (antimuscarinic and α-blocking actions).
: The concurrent use of
and an MAOI has resulted in a potentially life-threatening reaction in several patients, including
excitement, muscle rigidity, hyperthermia and unconsciousness
. Respiratory depression and hypertension or hypotension have also been seen. Similar interactions have been seen when
was taken with MAOIs. The manufacturers of many other opioids
contraindicate the concurrent use of MAOIs.
What receptors does morphine work on?
Morphine has a high affinity for µ receptors and lower affinity for δ and κ receptors.
What type of opioids are hydromorphone and oxymorphone?
Hydromorphone and oxymorphone are strong agonists useful in treating severe pain.
How does heroine work as an opioid analgesic?
Heroin (diacetylmorphine) is rapidly hydrolyzed to
, which, in turn, is hydrolyzed to
. Both heroin and 6-MAM are more liposoluble than morphine and enter the brain more readily. Current evidence
suggests that morphine and 6-MAM are responsible for the pharmacological actions of heroin. Heroin is mainly excreted in the urine, largely as free and conjugated morphine.
What receptor does meperidine work on?
Meperidine is predominantly a µ receptor agonist. Meperidine is no longer recommended for the treatment of chronic pain because of concerns over metabolite toxicity. Like other opioids, meperidine causes pupillary constriction and has effects on the secretion of the pituitary hormones similar to those of morphine.
In which patients is meperidine contraindicated?
Meperidine has significant antimuscarinic effects, which may be a contraindication if tachycardia would be a problem. It is also reported to have a negative inotropic action on the heart.
What are the side effects of meperidine and what is the metabolite that mediates these effects?
Large doses of meperidine repeated at short intervals produce tremors, muscle twitches, dilated pupils, hyperactive reflexes and convulsions. These excitatory symptoms are due
to the accumulation of the metabolite
, which has a half-life of 15-20 hours compared with 3 hours for meperidine. Since normeperidine is eliminated by both the kidney and the liver,
decreased renal or hepatic function increases the likelihood of such toxicity
What is the main drug reaction with meperidine?
The most prominent is an excitatory reaction ("
") with delirium, hyperthermia, headache, hyper- or hypotension, rigidity, convulsions, coma, and death. This reaction may be due to the ability of meperidine to block neuronal reuptake of serotonin and the resulting serotonergic overactivity. Therefore, meperidine should not be used in patients taking other serotonergic agents such as
What kind of opioid is fentanyl?
Fentanyl is a widely used opioid analgesic. It is primarily a µ agonist. It has rapid onset and short duration of action (15-30 minutes). Fentanyl is 100 times more potent than morphine, and sufentanil is 1000 times more potent than morphine.
What drugs are in the fentanyl subgroup?
The fentanyl subgroup now includes sufentanil, alfentanil, and remifentanil in addition to the parent compound, fentanyl.
What are fentanyl drugs used for?
Fentanyl and sufentanil have gained widespread popularity as
. The use of fentanyl and sufentanil in chronic pain treatment is widespread. The development of novel, less invasive routes of administration for fentanyl has facilitated the use of these compounds in chronic pain management.
that provide sustained release of fentanyl are available. An oral transmucosal formulation (
a fentanyl lozenge on a stick
) is approved for
treatment of breakthrough pain in cancer patients already taking strong opioids for persistent pain. Another transmucosal form of fentanyl for breakthrough pain is now available as an
effervescent buccal tablet
What kind of opioid drug is methadone?
Methadone is a synthetic, orally effective opioid that is approximately equal in potency to morphine, but induces less euphoria and has a longer duration of action. Methadone is a μ receptor agonist, an NMDA receptor antagonist, and a serotonin and norepinephrine reuptake inhibitor. These multiple mechanisms of action make methadone an interesting choice for chronic pain.
What is methadone used for?
Methadone substitution is the preferred method of managing opioid withdrawal for addicted patients because it has a
long half-life and less profound sedation and euphoria
. Due to the long half-life of methadone the abstinence syndrome is prolonged but less severe than that from a shorter-acting opiate such as heroin. These properties make methadone a useful drug for
detoxification and for maintenance of the chronic relapsing heroin addict
What are the side effects of methadone?
Methadone has no active metabolites and may be advantageous in patients with renal insufficiency. Dose-related QT interval prolongation, torsades de pointes and death have been reported with methadone.
What drug, other than methadone, can be used for the recovering heroine addict?
A related compound,
, which has an even longer half-life than methadone, has been approved by the FDA for use in detoxification clinics. This agent may be given once every 2-3 days.
What is the effect of levorphanol?
The pharmacological effects of levorphanol closely parallel those of morphine.
What class of opioids are codeine, oxycodone and hydrocodone? What are they used for?
Codeine, oxycodone and hydrocodone are mild to moderate antagonists. They are all somewhat less efficacious than morphine. These compounds are rarely used alone but are combined in formulations containing aspirin, acetaminophen, or other drugs. Codeine has low affinity for opioid receptors.
The analgesic effect of codeine is due to its conversion to morphine by CYP2D6
. However, its antitussive actions may involve distinct receptors that bind codeine itself.
What receptors does propoxyphene bind to?
Propoxyphene binds primarily to µ receptors.
How does the structure of propoxyphene relate to its function?
The dextro isomer of propoxyphene is used as an analgesic to relieve mild to moderate pain. The levo isomer is not analgesic, but it has antitussive action.
What are the side effects of propoxyphene?
Propoxyphene has an increased risk of
seizures and cardiac conduction abnormalities and should be avoided in the elderly
. The increasing incidence of deaths associated with its use and misuse has caused it to be scheduled as a controlled substance. In November 2010 the manufacturers of propoxyphene agreed to withdraw propoxyphene from the U.S. market at the request of the FDA, due to data showing that the drug can cause serious cardiotoxicity.
What is the mechanism of action of tramadol?
Tramadol is a weak µ agonist and a norepinephrine and serotonin reuptake inhibitor.
What is tramadol used for?
Tramadol is useful in neuropathic pain.
What are the contraindications with tramadol?
Tramadol is associated with an increased risk of
in patients with a seizure disorder and those taking medications that lower seizure threshold. Use of tramadol with other
(e.g., serotonin reuptake inhibitors,
tricyclic antidepressants or MAO inhibitors) should be avoided because it may precipitate a
What class of opioids are pentazocine, butorphanol, nalbuphine, and buprenophine?
Pentazocine, butorphanol, nalbuphine, and buprenophinemixed agonist-antagonists.
What is the use of mixed opioid agonist-antagonists?
The mixed opioid agonist-antagonists are potent analgesics in opioid-naive patients but precipitate withdrawal in patients who are physically dependent on opioids. They are useful for the treatment of mild to moderate pain. They were developed to reduce the addiction potential of the opioids while retaining the
analgesic potency of the drugs.
What receptors does pentazocine work on?
Pentazocine is a κ agonist and a µ antagonist/partial agonist.
What receptors does butorphanol work on?
Butorphanol is a κ agonist and a µ antagonist/partial agonist.
What receptors does nalbuphine work on?
Nalbuphine is a κ agonist and a µ antagonist.
What receptors does buprenorphine work on?
Buprenorphine is a partial µ agonist and a κ antagonist.
What is buprenorphine used for?
Buprenorphine is FDA-approved for the management of opioid addiction. Treatment is initiated with buprenorphine alone, followed by maintenance therapy with a combination of buprenorphine and naloxone to minimize abuse potential.
Why are mixed agonists-antagonists not used for the treatment of pain?
Mixed agonist-antagonists are poor choices for patients with severe pain, and are not recommended as routine analgesics, because their dosing is limited by a
Which mixed agonists-antagonists are associated with psychomimetic effects?
Also, the use of pentazocine, butorphanol and nalbuphine is associated with psychotomimetic effects. Psychotomimetic effects are relatively uncommon with buprenorphine.
Why should you not give a mixed opioid receptor drug (or partial agonist drug) with a pure agonist drug?
Care should be taken not to administer any partial agonist or drug with mixed opioid receptor actions to patients receiving pure agonist drugs, because of the unpredictability of both drugs' effects: *reduction of analgesia or precipitation of an
explosive abstinence syndrome may result*.
What class of opioids are naloxone and naltrexone?
Naloxone and naltrexone are opioid antagonists.
What receptors does naloxone and naltrexone work on?
They have high affinity for µ receptors. They have lower affinity for the δ and κ receptors but can reverse the action of agonists at δ and κ receptors.
What are naloxone and naltrexone used for?
The major application of naloxone is in the treatment of acute opioid overdose. Naltrexone has actions similar to those of naloxone. It has a longer duration of action than naloxone.
Because of its long duration of action, naltrexone has been proposed as a maintenance drug for addicts in treatment programs. Naltrexone decreases craving for alcohol in chronic alcoholics and it has been approved by the FDA for this purpose.
What opioid drugs are used as antitussives?
Dextrometorphan and codeine are antitussives. Opioid analgesics are among the most effective drugs available for the suppression of cough. This effect is often achieved at doses below those necessary to produce analgesia. The receptors involved in the antitussive effect appear to differ from those
associated with other actions of opioids.
What drug interaction can occur with dextrometorphan and codeine?
Dextrometorphan and codeine should be used with caution in patients taking MAOIs.
Can codeine and dextrometorphan, when used as an antitussive, also be used as an analgesic?
Codeine has a useful antitussive action at doses lower than those required for analgesia. Dextrometorphan has no analgesic effects in antitussive doses.
Why is dextrometorphan preffered over codeine?
Dextrometorphan is purported to be free of addictive properties, and produces less constipation than codeine. It is available in many over-the-counter products. Dextrometorphan has a significantly better adverse effect profile than codeine and is equally effective as antitussive.
What opioids are used as anti-motility agents?
Diphenoxylate and loperamide are opioid drugs used to treat diarrhea.
What receptors do diphenoxylate and loperamide act on to treat diarrhea?
They act by several different mechanisms, mediated principally through either µ or δ receptors on enteric nerves, epithelial cells, and muscle.
What are the side effects of diphenoxylate and what can be done to prevent them?
Prescription opioid agonist that has no analgesic properties in standard doses. Higher doses have central nervous system effects, and prolonged use can lead to opioid dependence. Commercial preparations commonly contain small amounts of atropine to discourage overdosage. The anticholinergic properties of atropine may contribute to the antidiarrheal action. Diphenoxylate is scheduled for minimal control (schedule V)
because the likelihood of its abuse is remote.
Why is loperamide safer than diphenoxylate?
Loperamide is a nonprescription opioid agonist that does not cross the blood-brain barrier and has no analgesic properties or potential for addiction. Tolerance to long-term use has not been reported.