OPIOIDS

Methadone

1. The synthetic narcotics are meperidine, methadone, fentanyl, remifentanil, alfentanil and sufentanil.

2. These are all potent mu-receptor, kappa-receptor and delta-receptor agonists.

Methadone

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.

OPIOIDS

Meperidine

Alfentanil

Remifentanil

Meperidine

1. First synthetic narcotic analgesic and has weak anticholinergic properties.

2. It increases myocardial work and should not be administered to patients with coronary artery disease.

3. Repetitive doses of meperidine may be associated with high levels of a metabolite (normeperidine) that may cause seizures.

4. 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

1. Short-acting agents

2. Alfentanil has a relatively small volume of distribution

3. Remifentanil, the shortest acting of these agents, has a very high clearance.

OPIOIDS

Agonist-Antagonist

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.

What are the differences between:

1. Naturally occurring narcotic analgesics

2. Semi-synthetic narcotic analgesics

3. Synthetic narcotic analgesics

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

1. 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. Example: codeine opiate derived from opium

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

3. Synthetic narcotic analgesics are: Fentanyl, Remifentanil, Sufentanil, Alfentanil, Meperidine, and Methadone

What are the differences between:

1. Opioid-receptor agonists

2. Antagonists

3. 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.

What are the differences between

1. Opioid-receptor agonists

2. Antagonists

3. 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-antagonist when administered alone produces analgesia, however if given to a patient who is taking a pure opioid agonist these drugs can antagonize analgesia.

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).

What are the differences between

1. Opioid-receptor agonists

2. Antagonists

3. 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 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

Describe the enkephalins, endorphins, and dynorphins.

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.

How is codeine structurally similar to morphine?

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

Codeine is not effective until it is converted to morphine in the liver, is this true or false?

True.

The reason this is important is that about 8% of people do not have the enzyme responsible for demethylating codeine; therefore, at least 1 out of 12 patients treated with codeine will be treatment failures.

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 an amine that is produced by a plant.

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.

Where do the names opium, morphine and papaverine come from?

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

During cardiac bypass surgery, the surgeon may inject papaverine around the mammary artery.

Why is this done?

Describe the cardiovascular effects may this produce and briefly describe the mechanism for these effects.

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.

Muscle relaxation may occur due to inhibition of cyclic nucleotide phosphodiesterase, increasing cyclic AMP.

How does the activity of the cytochrome P450 enzyme CYP2D6 affect the way individuals respond to codeine?

Why is this clinically important.

1. CYP2D6 is a member of the cytochrome P450 family (a mixed-function 2. oxidase system).

2. The function of most CYP enzymes is to catalyze the oxidation of organic substances.

3. 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.

1. Approximately 0 – 15% of codeine is O-demethylated to morphine,

2. Most active metabolite, which has an approximate 200-fold greater affinity for the mu opoid receptor when compared to codeine.

3. People who are poor metabolizers are unable to convert codeine to morphine efficiently so they may not experience pain relief.

4. Ultrametabolizers may metabolize codeine too efficiently which could lead to morphine intoxication.

How is meperidine different in its:

1. actions

2. toxicity

from other narcotics?

Some of the different actions of meperidine:

1. Structurally similar to atropine --> a mild atropine-like antispasmodic effects
2. Can be effective in suppressing postoperative shivering most likely d/t 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

How is meperidine different in its:

1. actions

2. toxicity

from other narcotics?

1. Meperidine is metabolized to normeperidine, an active metabolite and a compound capable of inducing seizures at high concentrations.

2. Normeperidine is only about half as effective as the parent compound meperidine as an analgesic, it can be neurotoxic and can cause significant CNS adverse effects.

3. Some of the CNS toxicity secondary to normeperidine is nervousness, hallucinations, tremors, myoclonus and generalized seizures.

4. Normeperidine is primarily eliminated renally and its half-life is about 5 – 10 times longer than that of meperidine depending on renal function.

5. Patients with impaired renal function can accumulate normeperidine in their system.
6. Meperidine is one of the most toxic narcotic analgesics. It increases myocardial work and should not be used in patients with CAD.

7. It has a very toxic metabolite (normeperidine) that can cause seizures with repetitive dosing (eg, PCA administration) or else in patients with renal failure.

What are the clinical effects of morphine?

1. Analgesia, euphoria, sedation, diminished ability to concentrate
2. N/V (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, pruritis, miosis
4. Increased pain threshold and modify the perception of noxious stimulation
5. Decreased sympathetic nervous system tone to peripheral veins, decreasing venous return, CO and BP
6. Coronary artery dilatation
7. Bradycardia from possible increased activity over the vagal nerves and depressant effect on the SA node
8. Histamine release
9. Dose dependent respiratory depression through agonist effect at mu2 receptors
10. In absence of hypoventilation, decrease cerebral blood flow and possibly ICP
11. Decreases propulsive peristaltic contractions of small and large intestines which can result in constipation
12. Can have delayed or prolonged effects due to its active metabolite M6G

What are the main metabolites of morphine?

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.