Opioid Analgesics & Antagonists

Opioid Analgesics & Antagonists

* Pain management

Opioid Analgesics & Antagonists

* Severe or chronic malignant pain opioids are the drugs of choice.
* Opioids are natural or synthetic compounds that produce morphine-like effects; opiates are drugs obtained from the juice of the opium poppy.
* All drugs in this category act through binding to specific opioid receptors in the CNS to mimic the effects of endogenous agents (endorphins & enkephalins) that eliminate many of the symptoms of a pain syndrome.
* Their anxiolytic and euphoric effects have led to their abuse.

Opioid Receptors

* Opioids interact stereospecifically with protein receptors on the membranes of certain cells in the CNS, on nerve terminals in the periphery and on cells of the gastrointestinal tract and the anatomic regions.
* The major effects of opioids are mediated through three receptor families: μ, κ and δ.
* Analgesic properties are mediated mainly via μ receptors and κ receptors of the dorsal horn of the spinal cord.
* Enkephalins interact more selectively with the δ receptors in the periphery.
* All three families are G-protein coupled receptors and inhibit adenylate cyclase.
* They are also involved in postsynaptic hyperpolarization (increasing K+ efflux) or reducing presynaptic Ca++ influx; this inhibits neuronal activity.

Receptor distribution

High densities of opioid receptors have been identified on peripheral nerve fibers, immune cells and five general areas of the CNS:

1. Brainstem: mediating respiration, cough, nausea & vomiting, maintenance of BP, papillary diameter and control of stomach secretion.

2. Medial thalamus: mediating poorly localized deep pain

3. Spinal cord: receptors located in the substantia gelatinosa are involved in the receipt & integration on sensory input leading to the attenuation of painful afferent stimuli.

Receptor distribution

4. Hypothalamus: mediating neuroendocrine secretion.

5. Limbic system: the greatest concentration of receptors are located in the amygdale, these receptors play a major role in emotional behavior & response and little analgesic effect.

Receptor distribution

6. Periphery: Peripheral nerve fibers bind opioids, they inhibit Ca+2 dependent release of excitatory, pro-inflammatory substances (substance P) from nerve endings

7. Immune cells: the role of these receptors in analgesia is undetermined.

Opioid Agonists

* The strongest naturally occurring analgesic drugs are found in opium from the poppy flower, morphine and less potent codeine. These drugs show a high affinity for the μ receptor and less affinity for the κ and δ receptors.

Morphine


Mechanism of Action:

* Opioids exert their major effects through interaction with central & peripheral opioid receptors, binding results in hyperpolarization, inhibition of nerve firing and presynaptic inhibition of transmitter release.
* Morphine acts at the κ receptors in lamina I & II of the substantia gelatinosa of the cord and decreases the release of substance P, it also inhibits the release of excitatory transmitters from nociceptive nerve terminals centrally and in the cord.

Actions:

Analgesia:

* Opioids cause pain relief by both raising the pain threshold at the spinal cord level and altering the central perception of pain. Awareness of pain remains but it loses its unpleasant character.

Euphoria:

* Opioids produce a sense of contentment and well being, this may be

related to stimulation of the central tegmental tract.

Respiration:

* Opioids cause respiratory depression by decreasing the sensitivity of central respiratory neurons to CO2. This occurs at therapeutic doses and as dose increases respiratory arrest will occur.

Suppression of cough reflex

* Antitussive properties do not correlate with analgesic or respiratory depression effects; this appears mediated via a different receptor complex.

Actions:

Miosis:

* This results from stimulation of μ and κ receptors located in the Edinger-Westphal nucleus of CN III, this is resistant to tolerance, pin point pupils remain after most other opioid effects have developed tolerance.

Emesis:

* Opioids directly stimulate the chemoreceptor trigger zone in the area postrema that causes vomiting.

GI tract:

* Opioids relieve diarrhea by decreasing gut motility and increasing the tone of intestinal smooth muscle. Constipation is also resistant to tolerance. Biliary spasm is exacerbated by increasing biliary tone with sphincter of Oddi spasm.

Cardiovascular:

* At large doses morphine produces hypotension & bradycardia.

Actions:

Histamine release:

* Morphine causes mast cell degranulation with the release of histamine causing urticaria, itching, diaphoresis and vasodilation. In asthmatics it may precipitate bronchospasm.

Hormonal Actions:

* Morphine inhibits the release of GnRH, CRH and deceases the release of LH, FSH & ACTH and β-endorphin. Testosterone and cortisol levels decrease. Prolactin and GH release are increased via suppression of dopamine levels centrally. ADH release is also diminished.

Therapeutic Uses

* Analgesia: Few drugs are as effective as morphine for the relief of pain.
* Treatment of diarrhea
* Anti-tussive: codeine and dextromethorphan are congeners with greater antitussive effects.
* Pulmonary edema: IV morphine dramatically relieves the dyspnea associated with pulmonary edema due to LV failure.

Pharmacokinetics

1. Administration: Morphine is poorly absorbed orally; codeine is a much more effective oral analgesic. Both undergo extensive first pass metabolism in the liver. Inhalation is an effective route but has found favor only with non-medicinal administration.

2. Distribution: Morphine readily enters all body tissues except the brain; morphine is the least lipid soluble of the opiates (fentanyl, methadone and heroin all enter the CNS much more quickly).

3. Metabolism: Conjugated in the liver, morphine–6-glucuronide is a much more potent analgesic; however morphine-3-glucuronide is less analgesic. Both are excreted in the urine with small amounts excreted in the bile. Hepatic & renal dysfunction both prolong the normal 4-6 hour duration of action when administered systemically.

Adverse effects

* Severe respiratory depression can occur and is the mechanism of dearth in most opiate overdose. Vomiting, dysphoria and allergic reactions are also common adverse effects.
* Caution must be exercised when opiates are used in those with liver or renal failure.

Tolerance & Physical Dependence

Repeated use produces tolerance to the effects of respiratory depression, analgesia, euphoria and sedation. Tolerance does not develop to miosis and constipation. Physical & psychological dependence readily occur with morphine and other opiates. Withdrawal induces a syndrome associated with autonomic, motor and psychological responses that are incapacitating, rarely are these life threatening.

Meperidine

* Meperidine (Demerol) is a synthetic opioid structurally unrelated to morphine.
* Mechanism: It binds to μ receptors with some binding at κ receptors.
* Actions: It causes respiratory depression similar to morphine but has no significant cardiovascular effect when given orally. IV administration produces a decrease in PVR resulting in increased peripheral blood flow. It causes papillary dilation via an atropine –like effect.

Meperidine

* Therapeutic uses: Severe acute pain, it lacks anti-tussive activity and produces less smooth muscle contraction/spasm than morphine.
* Pharmacokinetics: It is well absorbed form the GI tract; it is most often given IM. It has a shorter duration of action than morphine (2-4 hours). It is demethylated in the liver and excreted in the urine.
* Adverse effects: With large repeated doses normeperidine (demethylated meperidine) accumulates causing anxiety, muscle tremors and convulsions. It causes papillary dilation (vs. miosis with morphine) in large doses. There is cross-tolerance with other opioids.

Methadone

* This is a synthetic orally effective opioid that is equipotent to morphine but induces less euphoria and has a longer duration of action.
* Mechanism of action: Methadone binds to the μ receptor.
* Actions: Methadone is well absorbed orally and is an equipotent analgesic to morphine. It causes miosis, respiratory depression, biliary spasm and constipation just like morphine.

* Therapeutic uses: It is used for controlled withdrawal from heroin & morphine. Methadone is it self addictive but the withdrawal syndrome is somewhat milder but more protracted than with other opioids.
* Pharmacokinetics: Readily absorbed orally it is highly protein bound so remains in tissues for a prolonged period. It is transformed in the liver and excreted by the urine as mostly inactive metabolites.
* Adverse effects: similar to morphine particularly the risk of addiction

Fentanyl

* Chemically related to merperidine fentanyl has 100 times the analgesic potency of morphine. It has a rapid onset of action and a short duration (15-30 minutes. It can be used IV, epidurally or intrathecally. Transmucosal and transdermal preparations are available. Fentanyl is metabolized to an inactive metabolite by the cytochrome p4503A4 system. Drug metabolites are eliminated through the urine. Like morphine fentanyl causes miosis (vs. mydriasis). A particular risk of the transmucosal or transdermal routes is respiratory depression; these delivery routes create a reservoir of drug in the skin or mucosa.
* Sufentanil, Alfentanil & Remifentanil are related to fentanyl they differ in their potency and metabolic disposition. Sufentanil is even more potent than fentanyl.

Heroin


* Heroin is produced by the diacetylation of morphine which results in a three fold increase in its potency. The acetylation allows it to cross the BBB much more rapidly yielding a more pronounced euphoria. It may be used IV or smoked, both allow for rapid distribution, heroin is metabolized to morphine. There is no medical indication for its use in the US.

Moderate Agonists

Codeine

* This is a much less potent analgesic than morphine, it produces less euphoria and has much lower abuse potential and rarely produces physical dependence.
* It is an effective oral analgesic. It does possess significant antitussive effects at subanalgesic doses.
* Codeine is often formulated with either acetaminophen, aspirin of ibuprofen; care but be exerted when these are used with over the counter analgesic to avoid overdose with the non-opioid agent.
* A synthetic congener of codeine dextromethorphan lacks analgesic properties is an effective antitussive available without prescription.

Moderate Agonists

Oxycodone

* This is a semisynthetic derivative of morphine that is orally active; it too is formulated with over-the-counter analgesics. It is metabolized in the liver and excreted via the kidney. Controlled release forms of oxycontin requiring once or twice a day dosing are effective for chronic pain. Crushing these pills disrupts the sustained release mechanism resulting in acute intoxication consistent with opiate overdose.

Moderate Agonists

Hydrocodone is a semi-synthetic opioid derived from two of the naturally occurring opiates, codeine and thebaine. Hydrocodone is an orally active narcotic analgesic and antitussive. It is commonly available in tablet, capsule, and syrup form and is often compounded with other analgesics like acetminophen or ibuprofen

Moderate Agonists

Propoxyphene

* This is a derivative of methadone, it is used for mild to moderate pain; it has ~1/2 the potency of codeine.
* It is often formulated with another over-the-counter analgesic. The combination has greater effect than either drug alone.
* Toxic doses may produce cardio and pulmonary toxicity particularly when taken in combination with alcohol and/or sedatives in addition to CNS depression. Opioid antagonists can reverse the pulmonary and CNS effects but not the cardiotoxixity.

Mixed Agonist-Antagonist and Partial Agonists

Buprenorphine

* This agent is a partial agonist at μ receptors producing morphine-like effects in naïve users but precipitating withdrawal in morphine dependents.
* It is metabolized in the liver and excreted in the urine and bile. This agent may be taken sublingually or parenteral and possess a long duration of action.
* Adverse effects respiratory depression not reversible by naloxone, hypotension and nausea.
* Its main use is in opioid detoxification as its withdrawal syndrome appears less severe and of shorter duration than methadone. It is available outside of the specialized clinic allowed to dispense methadone for opiate withdrawal.

Antagonists

Opioid antagonists bind with high affinity to the μ, κ & δ receptors but fail to transducer. In normal individuals these agents produce no effect but in those with opiates present they induce an acute withdrawal syndrome.

A. Naloxone

* This agent is used to reverse the coma and respiratory depression associated wit opioid overdose. It competes at all receptors with much greater avidity than agonists. IV administration produces a reversal of CNS & respiratory depression within ~30 seconds. It has a relatively short T1/2 (60-100 minutes) so reversal will often abate requiring repeat administration. Binding affinity is 10X greater at the μ receptor than κ; this may explain how naloxone reverses respiratory depression but not analgesia (resulting from agonism of the κ- receptors in the spinal cord).

B. Naltrexone

* This agent has similar actions as naloxone but it is an oral agent with a much longer duration of action, a single dose is able to antagonize the effects of heroin for up to 48 hours.

Opioid Analgesics & Antagonists.ppt