Opioid Analgesics Flashcards
Mechanism of Action of Opioid Analgesics
MECHANISM OF ACTION
Opioid agonists produce analgesia by activating receptors located primarily in brain and spinal cord regions involved in transmission and modulation of pain.
CELLULAR ACTIONS OF OPIOIDS
The opioids have two well-established actions on neurons:
They close voltage-gated Ca2+ channels on presynaptic nerve terminals and thereby reduce neurotransmitter release.
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.
What are the three recepto types and their Physiologica Effect
RECEPTOR TYPES
Three major classes of opioid receptors have been identified in various nervous system sites and other tissues. The major classes are μ, δ and κ. The three are G protein linked receptors, coupled to inhibition of adenylyl cyclase, activation of receptor-operated K+ channels and suppression of voltage-operated Ca2+ channels.
RELATION OF PHYSIOLOGICAL EFFECTS TO RECEPTOR TYPE
The majority of currently available opioid analgesics act primarily at the μ receptor.
Analgesia, euphoria, respiratory depression, and physiological dependence result mainly from activation of μ receptors.
δ and κ receptors also contribute to analgesia, particularly at the spinal level.
Mixed agonist–antagonist compounds, with agonist selectivity for the κ receptor, were developed in the hope that they would have less addictive potential and respiratory depression than morphine and related drugs. In practice, for the same degree of analgesia, the same intensity of side effects occurs. Also, a “ceiling effect” limits the amount of analgesia attainable with these drugs. Some mixed agonist– antagonist drugs, such as pentazocine, butorphanol and nalbuphine, can cause severe psychotomimetic effects that are not reversible with naloxone (and thus may not be mediated by classical opioid receptors). These drugs also can precipitate withdrawal in opioid-tolerant patients, further limiting their clinical use.
What are the neural mechanisms of analgesia?
In spinal analgesia? In supraspinal analgesia? and peripheral analgesia?
The analgesic effects of opioids arise from their ability to directly inhibit the ascending transmission of nociceptive information from the spinal cord dorsal horn and to indirectly activate pain-inhibitory circuits that descend from the midbrain via the rostral ventromedial medulla to the spinal cord dorsal horn.
1. Spinal Analgesia
μ, δ and κ receptors are present in the dorsal horn of the spinal cord. Receptors are present on both spinal cord pain transmission neurons and presynaptically on the primary afferents that relay the pain message to them.
a. Opioids inhibit release of excitatory neurotransmitters (substance P and glutamate) from these primary afferents.
b. 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.
2. Supraspinal Analgesia
a. 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.*
* Part of the pain-relieving action of exogenous opioids involves release of endogenous opioid peptides. An exogenous agonist (e.g. morphine) may act primarily and directly at the μ receptor, but this action may evoke release of endogenous opioids that additionally act at δ and κ receptors. Thus, even a receptor-selective ligand can initiate a sequence of events involving multiple synapses and transmitters.*
3. 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.
Classification of Opioid Analgesics
1. Pure agonists. 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.
2. Partial agonists and mixed agonist-antagonists. These drugs combine a degree of agonist and antagonist activity on different receptors.
3. Antagonists. The most important examples are naloxone and naltrexone.
What are the CNS and Peripheral Effects of Opioids?
CNS EFFECTS
Analgesia: Opioids can reduce both the sensory and emotional components of pain, especially the emotional component.
Euphoria: Patients who receive IV morphine experience a pleasant floating sensation with lessened anxiety and distress. However, dysphoria may sometimes occur.
Sedation and drowsiness: Frequent effect of opioid action. Places ambulatory patients at risk for accidents.
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.
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.
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.
Truncal rigidity: Resulting from action at supraspinal levels.
Nausea and vomiting: Opioid analgesics can activate the brainstem chemoreceptor trigger zone.
PERIPHERAL EFFECTS
Hypotension: Opioids inhibit the vasomotor centre in the brainstem causing peripheral vasodilation; they also inhibit compensatory baroreflexes and increase histamine release.
GI tract: 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.
Biliary tract: Opioids contract biliary smooth muscle, which may result in biliary colic.
Genitourinary tract: Renal function is depressed due to decreased renal plasma flow.
Uterus: May prolong labour. Mechanism unclear, but both peripheral and central effects can reduce tone.
Neuroendocrine: Opioid analgesics stimulate release of ADH, PRL, and somatotropin but inhibit release of LH.
Pruritus: Flushing, warming of the skin, sweating and itching. Central effects and histamine release may be responsible.
Metabolism and Excretion of Opioids
Opioids are converted in large part to polar metabolites (mostly glucuronides), which are then excreted by the kidneys.
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 blood- brain barrier, and probably do not contribute significantly to the usual CNS effects of morphine given acutely.
However, the effects of these active metabolites should be considered in patients with renal impairment before the administration of morphine or hydromorphone, especially when given at high doses.
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.
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 seizures.
Fentanyl is metabolized by CYP3A4 in the liver. No active metabolites of fentanyl have been reported.
Codeine, oxycodone, and hydrocodone are metabolized in the liver by CYP2D6, resulting in the production of metabolites of greater potency. For example, codeine is demethylated to morphine.
EXCRETION OF OPIOIDS
Polar metabolites, including glucuronide conjugates of opioid analgesics, are excreted mainly in the urine. Small amounts of unchanged drug may also be found in the urine.
In addition, glucuronide conjugates are found in the bile, but enterohepatic circulation represents only a small portion of the excretory process.
Clinical Use of the Opioid Analgesics
Analgesia: Treatment of relatively constant moderate to severe pain is the main indication of opioid analgesics.
Acute 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.
Cough: The opioid derivatives most commonly used as antitussives are dextrometorphan, and codeine.
Diarrhea: Diarrhea from almost any cause can be controlled with opioid analgesics. However, if diarrhea is associated with infection, chemotherapy is indicated. Loperamide and diphenoxylate are the most commonly used drugs to control diarrhea.
Applications In Anesthesia:
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 column.
Adverse Effects of Opioids
Adverse effects of the opioid analgesics include nausea, vomiting, sedation, itching, constipation, urinary retention, hypotension and respiratory depression.
The most common adverse effects reported with the use of opioid analgesics are nausea, vomiting, sedation, itching and constipation.
TOLERANCE AND DEPENDENCE
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.
ADDICTION
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.
Contraindications and Cautions in Therapy
USE OF PURE AGONISTS WITH WEAK PARTIAL AGONISTS
When a weak partial agonist such as pentazocine is given to a patient also receiving a full agonist (eg, morphine), there is a risk of diminishing analgesia or even inducing a state of withdrawal; combining full agonist with partial agonist opioids should be avoided.
USE IN PATIENTS 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.
USE DURING PREGNANCY
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.
USE IN PATIENTS WITH IMPAIRED PULMONARY FUNCTION
In patients with borderline respiratory reserve, the depressant properties of the opioid analgesics may lead to acute respiratory failure.
USE 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.
USE 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.
USE IN PATIENTS WITH ENDOCRINE DISEASE
Patients with adrenal insufficiency (Addison’s disease) or hypothyroidism (myxedema) may have prolonged and exaggerated responses to opioids.
Drug Interations with Opioids
Sedative-hypnotics: Increase CNS depression, particularly respiratory depression.
Antipsychotics: Increase sedation. Variable effects on respiratory depression. Accentuation of CV effects (antimuscarinic and α-blocking actions).
MAO inhibitors: The concurrent use of meperidine 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 tramadol was taken with MAOIs. The manufacturers of many other opioids contraindicate the concurrent use of MAOIs.
Morphine
STRONG AGONISTS
MORPHINE
High affinity for μ receptors and lower affinity for δ and κ receptors. There are now many compounds with pharmacological properties similar to those produced by morphine, but none has proven to be clinically superior in relieving pain. Morphine remains the standard against which the new analgesics are measured.
Hydromorphone and Oxymorphone
STRONG AGONISTS
HYDROMORPHONE AND OXYMORPHONE
Strong agonists useful in treating severe pain.
Heroin
STRONG AGONISTS
HEROIN
Heroin (diacetylmorphine) is rapidly hydrolyzed to 6-monoacetylmorphine (6-MAM), which, in turn, is hydrolyzed to morphine. 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.
Meperidine
STRONG AGONISTS
MEPERIDINE
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.
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.
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 normeperidine, 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.
DRUG INTERACTIONS
The most prominent is an excitatory reaction (“serotonin syndrome”) 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 MAO inhibitors.
Fentanyl
STRONG AGONISTS
FENTANYL
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. Fentanyl has gained widespread popularity as anesthetic adjuvants.
The use of fentanyl 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. Transdermal patches 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.
