INTRODUCTION TO THE PHARMACOLOGY OF OPIOID DRUGS

[Pages:15]INTRODUCTION TO THE PHARMACOLOGY OF OPIOID DRUGS

Monsheel Sodhi B.Pharm. Ph.D. msodhi@luc.edu

Objectives:

1. To describe the mechanisms of action of the major drugs modulating the opioid system. 2. To describe the major opioid receptors- structure, signaling mechanisms and ligand

selectivity. 3. To describe how pharmacological activation of the opioid receptor signaling pathways

promotes analgesia. 4. List the indications for the major opioid receptor agonists, partial agonists and

antagonists. 5. To understand the adverse effects of opioid drugs and indications in which these have

therapeutic use. 6. To describe any clinically relevant drug interactions with the major drugs acting on the

opioid receptor system. 7. To describe the pharmacokinetic factors influencing the efficacy of opioid drugs.

Note: This lecture is introductory. The objectives are stated. This lecture cannot substitute for the years of training required for expertise in pain management or anesthesia. That level of detail is not possible within one hour or at this stage of your training.

You do not have to memorize the information in every slide or chemical structures. It is preferable that you understand the mechanisms. With this understanding, you will be able to deduce the pharmacological effects of the drugs. Pictures are included to aid your understanding.

Key Terminology

? Opioid = any substance, endogenous or synthetic, that produces morphine-like effects that are blocked by antagonists such as naloxone.

? Opiate = compounds that are found in the opium poppy (e.g. morphine). ? Narcotic = induces sleep (original definition).

Drugs covered in this lecture:

I. Pure agonists: e.g. codeine, morphine, fentanyl

II. Mixed agonist/antagonist opioid drugs: e.g. butorphanol, nalbuphine, pentazocine, buprenorphine

III. Opioid antagonists: e.g. naloxone, naltrexone, methylnaltrexone

Outline

o Mechanism of opioid analgesia o Opioid sensitive pain pathways o Molecular mechanisms for opioid action in the spinal cord o Pharmacological effects of opioid receptors o Effects of opioid receptor agonists o Pure opioid agonists o Mixed agonist/antagonist opioid drugs o Adverse effects of opioid agonists o Opioid receptor antagonists o Opioid withdrawal o Therapeutic uses for the adverse effects of opioids o Pharmacokinetics of opioid drugs

Mechanism of Opioid Analgesia

Opioid receptor in the cell membrane, indicating 7 transmembrane domains

The endogenous ligand or drug binds to the opioid receptor and activates an inhibitory G protein, resulting in multiple effects, which are primarily inhibitory.

? Opioid receptors are inhibitory G protein-coupled receptors (GPCRs) o Opioid receptor stimulation results in inhibition of neuronal activity. o The activities of adenylate cyclase and the voltage-dependent Ca 2+ channels are depressed. The inwardly rectifying K + channels and mitogen activated protein kinase (MAPK) cascade are activated. o Another major function of G protein-coupled receptors is to control ion channel function directly by mechanisms that do not involve second messengers such as cAMP or inositol phosphates. Direct G protein?channel interaction, through the subunits of Gi and Go proteins, appears to be a general mechanism for controlling K+ and Ca2+ channels. o Similar mechanisms operate in neurons, where opioid analgesics reduce excitability by opening certain K+ channels, known as G protein- activated inwardly rectifying K+ channels (GIRK) ? or by inhibiting voltage-activated N and P/Q type Ca2+ channels and thus reducing neurotransmitter release.

Opioid-sensitive pain pathways

Two pain pathways between periphery and CNS:

1. Ascending pain pathway Opioid receptor stimulation inhibits the transmission of excitatory neurons, blocking the transmission of pain signals

2. Descending pain pathway Opioid receptor stimulation disinhibits the inhibitory neurons. This activates the inhibitory pathway, which blocks the transmission of pain signals

Stimulation of opioid receptors in the ascending and descending pain pathways results in analgesia.

Four sites where opioids activate opioid receptors to relieve pain:

Ascending pathway:

1. First order afferents: ORs in periphery block nociceptor activation + inhibit inflammatory mediator release (bradykinin, serotonin, prostaglandins)

2. ORs on second-order pain transmission cells blocks ascending transmission of pain signal (blockade of excitatory neurons).

3. ORs at C-fiber terminals in spinal cord, blocks release of pain neurotransmitters

Descending pathway:

4. ORs in midbrain, activate descending systems (through disinhibition of GABA neurons)

Molecular mechanisms for opioid actions in the spinal cord.

Analgesia by inhibition of ascending pain pathway

The primary afferent neuron (cell body not shown) originates in the periphery and carries pain signals to the dorsal horn of the spinal cord, where it synapses via glutamate and neuropeptide transmitters (substance P and CGRP) with the secondary neuron. Pain stimuli can be attenuated in the periphery (under inflammatory conditions) by opioids acting at -opioid receptors (MOR) or blocked in the afferent axon by local anesthetics (not shown). Action potentials reaching the dorsal horn can be attenuated at the presynaptic ending by opioids and calcium blockers, by 2 agonists, and possibly, by drugs that increase synaptic concentrations of norepinephrine by blocking reuptake. Opioids also inhibit the postsynaptic neuron, as do certain neuropeptide antagonists acting at tachykinin (NK1) and other neuropeptide receptors.

Analgesia by disinhibition of descending pain pathway

Brainstem local circuitry underlying the modulating effect of -opioid receptor (MOR)?mediated analgesia on descending pathways. The pain-inhibitory neuron is indirectly activated by opioids (exogenous or endogenous), which inhibit an inhibitory (GABAergic) interneuron. This results in enhanced inhibition of pain transmission in the dorsal horn of the spinal cord.

Pharmacological Effects of Opioid Receptor Stimulation

*This information is critical for your understanding of the opioid drugs. If you know the binding target(s) of the specific opioid drug of interest, you can deduce its pharmacological effects e.g. stimulation of the kappa receptor should not lead to euphoria.

Mu () or MOR Analgesia (supraspinal 1) Respiratory depression (2) Euphoria (2) Miosis Physical dependence (2) Sedation Inhibition of gastrointestinal motility

Delta () or DOR Analgesia (spinal) Respiratory depression

Inhibition of gastrointestinal motility

Kappa () or KOR Analgesia (spinal, peripheral)

Dysphoria Miosis

Sedation

Effects of opioid receptor agonists

Therapeutic use Pain management Anesthesia, sedation Anti-diarrheal Antitussive Treatment of dyspnea Adverse effects

Pharmacological Effect

Analgesia Sedation tone in intestinal muscle + secretions Depression of cough reflex Respiratory depression Nausea and vomiting Urinary retention Neurotoxicity Tolerance, dependence, addiction Paradoxical pain Pruiritis

I. Pure Opioid Agonists

a. Morphine i. Morphine is a full agonist at the (mu)-opioid receptor, the major analgesic opioid receptor. Opioids may also differ in receptor binding affinity. For example, morphine exhibits a greater binding affinity at the opioid receptor than does codeine. ii. Therapeutic uses: analgesia, dyspnea, anti-diarrheal (in suspension with kaolin), cough suppressant

iii. t1/2 of morphine is ~2 hrs iv. Excreted by kidney b. Codeine i. Derived from morphine ii. ~60% as effective orally vs. parenterally for analgesia iii. Greater oral efficacy than morphine iv. Antitussive ? codeine linctus, pholcodine v. t1/2 is 2-4 hrs vi. Metabolized by the liver c. Drugs used in anesthetics and severe pain i. Synthetic opioids similar to other mu receptor agonists ii. Fentanyl, sufentanil, remifentanil, and alfentanil iii. Important in anesthetic practice because they have a short time to peak

analgesic effect, rapid termination of effect after small bolus doses, cardiovascular safety, and capacity to significantly reduce the dosing requirement for volatile agents iv. Fentanyl also used in severe pain states ? transdermal patches, trans buccal absorption, epidural for post-op or labor

1. The use of epidural opioids and local anesthesia allows for a lower dosage of both to be used

II. Mixed Agonist/Antagonist Opioid Drugs

a. Butorphanol ? kappa receptor agonist and mu receptor antagonist i. Similar to pentazocine and nalbuphine ii. Treatment of acute pain (e.g. postoperative) iii. CV side effects so less useful than morphine or meperidine in MI or heart failure iv. Nasal formulation is effective analgesic, including for migraine pain v. Can cause dizziness and/or physical dependence

b. Nalbuphine ? kappa receptor agonist and mu receptor antagonist i. Effects resemble pentazocine but fewer dysphoric side effects ii. Nalbuphine hydrochloride used for analgesia iii. Kappa agonist relatively more effective in women than in men iv. Safe in CV patients v. Side effects include sedation, sweating, headache, and psychotomimetic at high doses vi. Physical dependence will occur with prolonged use, withdrawal similar to pentazocine.

c. Pentazocine ? kappa receptor agonist, week mu receptor agonist i. CNS effects similar to morphine ii. Analgesic, moderate to severe pain iii. Pre-operative medication and supplement to anesthesia iv. Dysphoria and psychotomimetic effects at high doses ? reversed by naloxone

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