An opioid is a natural or synthetic compounds that acts by binding to specific opioid receptors in the CNS to produce effects that mimic the action of endogenous peptide neurotransmitters. The term Narcotic refers to any substance that induces sleep, insensibility, or stupor and refers more to a side effect than an action of a drug.

What are the differences between naturally occurring narcotic analgesics, semi-synthetic narcotic analgesics and synthetic narcotic analgesics?

 How would you classify these agents: morphine, codeine, diacetylmorphine (heroin), fentanyl, remifentanil, sufentanil, alfentanil, meperidine, buprenorphine, methadone, dihydromorphone (dilaudid)?

Naturally occurring narcotic analgesics are natural compounds that bind to specific sites on the opioid receptors of the CNS to produce effects that mimic the action of endogenous peptide neurotransmitters. An example of this is codeine which is an opiate derived from opium.

Semi synthetic narcotics are derived by altering chemicals contained in opium and are produced by chemically treating the natural alkaloid. Two examples are diacetylmorphine (heroin) and dihydromorphone (dilaudid). 

The synthetic narcotics are all potent mu-receptor, kappa-receptor and delta-receptor agonists.Examples of synthetic narcotic analgesics are: Fentanyl, Remifentanil, Sufentanil, Alfentanil, Meperidine, and Methadone. Synthetic narcotics are man-made and do not have a similar structure. They are structurally different from naturally occuring narcotic analgesics.

What are the differences between opioid-receptor agonists, antagonists, and partial-agonists?

How would you classify these agents: morphine, codeine, diacetylmorphine (heroin), fentanyl, remifentanil, sufentanil, alfentanil, meperidine, buprenorphine, methadone, dihydromorphone (dilaudid), butorphanol (stadol), nalbuphine (nubain), pentazocine (talwin)?

An opioid agonist activate mu and kappa receptors. By activating these receptors, the agonist can produce analgesia, euphoria, sedation, respiratory depression, physical dependence, constipation, and other effects. Examples of agonists are: Codeine, Fentanyl, Sufentanil, Alfentanil, Meperidine, Methadone, Diacetylmorphine (Heroin), and Dihydormorphine (dilaudid).

An opioid agonist-antagonist when administered alone produces analgesia, however if given to a patient who is taking a pure opioid agonist these drugs can antagonize analgesia.  These drugs may precipitate an acute abstinence (withdrawal) reaction if administered to a narcotic addict.Examples of agonist-antagonist include: Pentazocine (Talwin), buprenorphine, butorphanol (Stadol), and nalbuphine (Nubain). Agonists/antagonists may be agonists at one set of receptors (eg, kappa) and antagonists at other receptors (eg, mu).

An opioid antagonist acts as a antagonist at mu and kappa receptors. These drugs do not produce analgesia or any of the other effects caused by opioid agonists, their principle use is for reversal of respiratory and CNS depression caused by overdose with opioid agonists.Examples of a opioid antagonist is naloxone (Narcan) and naltrexone. These agents may also precipitate an acute abstinence (withdrawal) reaction if administered to a narcotic addict.

The body has three families of peptides that have opioid-like properties. These families are named enkephalins, endorphins, and dynorphins.

 The enkephalin is a pentapeptide that interacts more selectively with the δ receptors in the periphery and regulates norciception. The endorphins are produced by the pituitary gland and the hypothalamus during exercise, excitement, pain, consumption of spicy food, love and orgasm, and they resemble the opiates in their abilities to produce analgesia and a feeling of well-being. Dynorphins exert their effects primarily through the κ-opioid receptor (KOR), a G-protein-coupled receptor. Dynorphin has been shown to be a modulator of pain response.

Describes mu- kappa- and delta receptors.

 Where are these receptors located, what are their endogenous ligands, and list drugs that stimulate these receptors.

Mu and Delta receptors are opioid receptors. All opioid receptors are protein receptors found on the membrane of certain CNS cells, on nerve terminals in the peripheral nervous system and on cells in the GI tract. In the brain they are found in the brainstem and thalamus. They are also found in the spinal cord, hypothalmus and limbic system.

Mu 1=analgesia and physical dependance

Mu 2=respiratory depression, miosis, euphoria, reduced GI motility, Physical dependence

Kappa=analgesia, sedation, miosis, inhibition ADH release, dysphoria

Endogenous ligands: mu receptor = morphine. Delta receptor = enkephalins.

Drugs Stimulated by mu receptors: Morphine, Meperidine, Methadone, Alfentail, Fentanyl, Heroin, Remifentanil and Tamadol. Pentazocine is a weak agonist, Buprenorphine is a partional agonist.

Drugs stimulated by Delta receptor: I couldn't find any. Research I did said not pure Delta agonists were clinically available for humans.

Where is codeine naturally found?

How is it structurally similar to morphine?

Codeine is made from the milky juice of unripe seeds of the opium poppy plant. (Poppies). 

Codeine is morphine with a methyl group (-CH3) attached.

Opium is not a single compound but an extract of the immature seeds of the opium poppy, Papaver somniferum. This extract contains up to 10% morphine, the opiate alkaloid, which is processed to produce diamorphine (better known as heroin). The resin also includes codeine and non-narcotic alkaloids, such as papaverine and noscapine. The source of opium is the poppy. Common name: white poppy, opium poppy. The opium alkaloids are sometimes called “phenanthrenes”.

 What is an alkaloid?

Which alkaloid was the first to be isolated (or purified)?

The names of many alkaloids end in what 3 letters?

An alkaloid is, strictly speaking, an amine that is produced by a plant. However, the term has been extended to amines produced by animals and fungi as well. The name derives from the word alkaline originally- the term was used to describe any nitrogen containing base.

Alkaloids are usually derivatives of amino acids, and many have a bitter taste. They are found as secondary metabolites in plants (such as potatoes and tomatoes), animals (such as shellfish), and fungi. In many cases, they can be purified from crude extracts by acid-base extraction.

The first individual alkaloid, morphine, was isolated in 1804 from poppy (Papaver somniferum).

The names of many alkaloids end in “ine” (eg, atropine, meperidine, neostigmine, codeine, morphine, etc.)

The name opium comes from the Greek opion.

Morphine is named morphium after Morpheus, the Greek god of dreams.

Papaverine is derived from Latin “poppy” and added “ine” from which the Greek paparouna originated.

Papaverine is naturally occuring alkaloid in opium. It gets its name from the name of the opium poppy = papaver somniferum. Note that papaverine is a PDE inhibitor and these vasodilating properties are similar to those of other PDE inhibitors (eg, milrinone = primacor).

Papaverine is a nonxanthine phosphodiesterase inhibitor used for for the relief of cerebral and peripheral ischemia associated with arterial spasm and myocardial ischemia complicated by arrhythmias. The main actions of papverine are exerted on cardiac and smooth muscle. Papaverine acts directly on the heart muscle to depress conduction and prolong the refractory period. The muscle cell is not paralyzed by papverine and still responds to drugs and other stimuli causing contraction. The antispasmodic effect is a direct one, and unrelated to muscle innervation. Papaverine is mainly devoid of effects on the central nervous system. It relaxes the smooth musculature of the larger blood vessels, especially coronary, systemic peripheral, and pulmonary arteries. In the above scenario, Papaverine is used as a smooth muscle spasmolytic to assist in maintaining graft patency (from spasm). Muscle relaxation may occur due to inhibition of cyclic nucleotide phosphodiesterase, increasing cyclic AMP.

CYP2D6 is a member of the cytochrome P450 family (a mixed-function oxidase system). The function of most CYP enzymes is to catalyze the oxidation of organic substances. This enzyme, CYP2D6, shows the largest phenotypical variability among the CYPs which means that depending on the genetic make-up of the person, this enzyme can have different observable characteristics or traits. The CYP2D6 function in any particular person can vary between being a poor metabolizer to an ultra metabolizer of certain drugs.

CYP2D6 has a role in the metabolism of codeine. Approximately 0 – 15% of codeine is O-demethylated to morphine, the most active metabolite, which has an approximate 200-fold greater affinity for the mu opoid receptor when compared to codeine. People who are poor metabolizers are unable to convert codeine to morphine efficiently so they may not experience pain relief. Ultrametabolizers may metabolize codeine too efficiently which could lead to morphine intoxication.

Here is a list of drugs metabolized by CYP2D6: Amiodarone (Cordarone), Bupropion (Wellbutrin), Chlorpheniramine (Chlor-Trimeton), Chloroquine (Aralen), Chlorpromazine (Thorazine), Cinacalcet (Sensipar), Diphenhydramine (Benadryl), Duloxetine (Cymbalta), Fluoxetine (Prozac), Halofantrine (Halfan), Haloperidol (Haldol), Imatinib (Gleevec), Paroxetine (Paxil), Perphenazine (Trilafon), Propafenone (Rythmol), Propoxyphene (Darvon), Quinacrine (Atabrine), Quinidine (Quinidex, etc), Quinine, Terbinafine (Lamisil).

Note: for active drugs, patients with absent CYP2D6 will have prolonged drug effect (decreased clearance). Most of these drugs are already active so they will last longer.

In the case of codeine, codeine is not as potent as its metabolite (morphine) so these patients will have a diminished response to codeine.

Some of the different actions of meperidine:
1. Structurally similar to atropine so it possesses a mild atropine-like antispasmodic effects
2. Can be effective in suppressing postoperative shivering most likely due to stimulation of kappa receptors and a drug induced decrease in the shivering threshold
3. Not useful for the treatment of diarrhea or as an antitussive
4. Can cause increases in heart rate
5. Large doses can result in decreases in myocardial contractility
6. Delirium and seizures can reflect the accumulation of normeperidine which has stimulating effects on CNS
7. Does not cause miosis but rather tends to cause mydriasis

Toxicity:

Meperidine was the first synthetic narcotic analgesic and has weak anticholinergic properties. It increases myocardial work and should not be adminitered to patients with coronary artery disease. One usual feature about meperidine is that has strong membrane stabilizing properties (this is a local-anesthetic like effect).

Repetitive doses of meperidine may be associated with high levels of a metabolite (normeperidine) that may cause seizures. In general, meperidine should be avoided in patients with a seizure disorder.

Normeperidine is only about half as effective as the parent compound meperidine as an analgesic, however, it can be neurotoxic and can cause significant CNS adverse effects. Some of the CNS toxicity secondary to normeperidine is nervousness, hallucinations, tremors, myoclonus and generalized seizures.

Normeperidine is primarily eliminated renally and its half-life is about 5 – 10 times longer than that of meperidine depending on renal function. Patients with impaired renal function can accumulate normeperidine in their system.

Meperidine is one of the most toxic narcotic analgesics. It increases myocardial work and should not be used in patients with CAD. It has a very toxic metabolite (normeperidine) that can cause seizures with repetitive dosing (eg, PCA administration) or else in patients with renal failure.

1. Analgesia, euphoria, sedation, diminished ability to concentrate
2. Nausea, vomiting (partially due to stimulation of the chemoreceptor trigger zone in the floor of the fourth ventricle delayed gastric emptying), feeling of body warmth, heaviness of the extremities
3. Dryness of mouth
4. Pruritus
5. Increased pain threshold and modify the perception of noxious stimulation
6. Decreased sympathetic nervous system tone to peripheral veins, decreasing venous return, cardiac output and bloodpressure
7. Coronary artery dilatation
8. Bradycardia from possible increased activity over the vagal nerves and depressant effect on the SA node
9. Histamine release
10. Dose dependent respiratory depression through agonist effect at mu2 receptors
11. In absence of hypoventilation, decrease cerebral blood flow and possibly ICP
12. Miosis
13. Decreases propulsive peristaltic contractions of small and large intestines which can result in constipation
14. Can have delayed or prolonged effects due to its active metabolite M6G

1. Morphine – 3 – glucuronide (M3G)
2. Morphine – 6 - glucuronide (M6G)

**M6G is an active metabolite and an opioid agonist believed to be approximately 2 – 4 times more potent than morphine.

For the test

You are not responsible for knowing the trade names of any drugs in this course.)

The synthetic narcotics are meperidine, methadone, fentanyl, remifentanil, alfentanil and sufentanil. These are all potent mu-receptor, kappa-receptor and delta-receptor agonists. Meperidine was the first synthetic narcotic analgesic and has weak anticholinergic properties. It increases myocardial work and should not be administered to patients with coronary artery disease. Repetitive doses of meperidine may be associated with high levels of a metabolite (normeperidine) that may cause seizures. In general, meperidine should be avoided in patients with a seizure disorder. One usual feature about meperidine is that has strong membrane stabilizing properties (this is a local-anesthetic like effect). Alfentanil and remifentanil are short-acting agents: alfentanil has a relatively small volume of distribution; remifentanil, the shortest acting of these agents, has a very high clearance.

Methadone is a potent mu-agonist that has a slow clearance and large volume of distribution therefore it has a very ______ duration of action. Methadone is used for analgesia and to treat opiate addiction. The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with opiates.

Agonists-Antagonists: Buprenorphine (Buprenex) is a semisynthetic, mu-receptor partial agonist. Butorphanol (Stadol) and nalbuphine (Nubain) are kappa-agonists and very weak mu-agonists (practically speaking, these two agents are mu-antagonists). Pentazocine (Talwin) is a mu-antagonist, kappa-agonist, delta-agonist.

What is the difference between an opioid and a narcotic?

An opioid is a natural or synthetic compounds that acts by binding to specific opioid receptors in the CNS to produce effects that mimic the action of endogenous peptide neurotransmitters. The term Narcotic refers to any substance that induces sleep, insensibility, or stupor and refers more to a side effect than an action of a drug.