I HISTORY OF OPIOID ANALGESICS (ANALGESIC RELIEF OF

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I. History of Opioid Analgesics (analgesic = relief of pain = antinociceptive)

A. Writings from 200 BC describe use of opium in medicine

B. May have been used by Sumerian culture as early as 3500 BC

II. Origin of Drug

A. The opium poppy (a flowering plant) produces a bud which secretes a white, latex. It is from this juice that opium is derived.

1. The word "opium" comes from the Greek word "opus" meaning juice.

2. The word "narcotic" comes from the Greek word "narcos" meaning "stupor".

B. Opium is a mixture of more than twenty alkaloids. Alkaloids are natural products which contain nitrogen.

1. Morphine is the most abundant such alkaloid in the mixture, comprising around 10%

a. Although people have been using opium for thousands of years, purified morphine was first isolated in the 19th century.

b. The word "morphine" comes from "Morpheus", the Greek God of dreams

2. Codeine, a simple analog of morphine, is also present, and comprises around 1%

III. Targets of opioid analgesics in the body

A. These drugs act in the Central Nervous System, thus must cross the blood-brain barrier

B. The receptors for the opioids are also targeted by some endogenous peptides, known as "endorphins"

C. The endorphins, like the opioid alkaloids, also relieve pain

D. Structurally, these peptides share the following sequence, beginning at the N-terminus of the peptide: H2N-Tyr-Gly-Gly-Phe-(Met or Leu)-

E. The actual physiological roles of these peptides are still being investigated. They may be neurotransmitters, modulators of neurotransmitters, or neurohormones.

F. Opioid receptors are divided into at least three groups: , , and .

G. Current clinically used products, including morphine, target the  receptor.

H. All of these receptors are G proteins. These particular G proteins operate to activate potassium channels and also to close voltage gated calcium channels.

III. Side Effects of Morphine

A. Respiratory Depression

B. Euphoria

C. Constipation

- Reduced intestinal secretion

- Reduced propulsive peristaltic waves

- Patient pays less attention to normal sensory stimuli to defecate

D. Tolerance

E. Addiction

F. Reduced sexual libido (in both men and women)

G. Reduced tendency to cough (antitussive effect)

H. Overall effect is immunosuppression, although how this happens is complex.

1. Increased susceptibility to infection and also increased spread of tumors

2. Opioid addicts are very susceptible to infection (e.g. HIV and also tuberculosis)

I. Miosis (constriction of the pupils)

IV. Administration

A. Parenterally (intravenously, intramuscularly, and subcutaneously)

B. Orally

1. However, oral morphine is only about 10% bioavailable as is intravenous morphine)

2. By contrast, oral codeine is about 60% bioavailable as is parenterally administered codeine.

C. Rectally

D. Transdermally (only utilized for non-polar opioids)

V. Structure Activity Relationships

A. Morphine is prototypical opioid

1. Show structure of both morphine and codeine

2. The 3-position hydroxy group is necessary for binding to the receptor

3. Codeine is 3-methoxy derivative and is only about 0.1% as active as morphine in LABORATORY experiments, but has 20% (or 60%, depending on source) activity of morphine IN VIVO

a. Codeine itself has little affinity for the opioid receptor. However, the antitussive receptors, which are quite different from the antinociceptive receptors

b. The reason for this is that the methyl group is metabolically removed in the liver to produce morphine

- This demethylated is achieved by a class of enzymes known as the cytochrome P450's. The particular cytochrome P450 involved in this transformation is known as CYP2D6

- There are polymorphisms of this enzyme within the population, thus different individuals may have different susceptibilities to codeine as an analgesic.

- Asians, for example have less ability to demethylate codeine than do Caucasions.

B. The 6-position hydroxy group

1. Not necessary for analgesic activity

2. Blocking the 6-position group can improve ability to penetrate the blood-brain barrier

3. Show structure of Heroin (diamorphine, diacetylmorphine)

a. Heroin was the very first prodrug

b. The removal of the two polar O-H groups permits very rapid penetration of the blood- brain barrier

c. Subsequent to penetration of the blood-brain barrier, the enzymatic hydrolysis of the acetoxy groups re-liberates the free O-H groups (particularly the C3 OH group) and generates an active drug

d. Heroin is utilized in treatment of pain in terminal cancer patients (but not in the U.S.A.)

4. 6-Acetylmorphine is very dangerous drug, and banned in most countries

a. Less polar than morphine

b. Therefore, can penetrate blood-brain barrier much more rapidly than morphine

c. More rapidly acting than Heroin, since it does not need to wait for the deprotection of 3- position OH group to become active

5. Commercially important compounds

a. Hydrocodone

b. Hydromorphone

c. Oxycodone

d. Oxymorphone

6. Nitrogen group is essential for activity.

a. Must be capable of having free amine in order to cross blood-brain barrier, but interacts with receptor as quaternary ammonium salt.

b. Adding groups to nitrogen

R = Et, Pr, allyl : Antagonism increases

R = Butyl : Zero activity

R = pentyl, hexyl : Agonists

R = CH2CH2Ph : V. powerful agonist with 14x activity with respect to morphine

c. Structures of antagonists of morphine

1. Nalorphine

2. Naloxone

3. Naltrexone

d. Antagonists are very useful in treating overdoses to avoid death by suffocation and to prevent addicts from returning to their habits. Naloxone is usually the drug of choice, but must be used cautiously as it may precipitate withdrawal in dependent subjects and cause cardiovascular side effects.

V. Related Analgesics of Importance

A. 4-Phenylpiperidines (4-phenylpiperidines): Made by removing rings B, C, and D of Morphine

1 Meperidine (demerol)

2 Fentanyl

B. Methadone

1. Discovered in Germany during WWII

Similary to morphine in potency, but has better oral potency and longer duration. Often used in Hospice Program for cancer patients

C. Loperamide HCl (Imodium AD)

Anti-diarrheal agent (low abuse potential and non-addictive)

VI. Analgesic Receptors

A. Mu () Receptor: Analgesia, Euphoria, and addiction. Respiratory Depression

B. Kappa Receptor (): Analgesia with none of the side effects

C. Delta Receptor (): Where brain's natural painkillers, the enkephalins, interact

VII. The Enkephalins

a. Produced in the brain

b. First Such Structures to be discovered:

H-Tyr-Gly-Gly-Phe-Met-OH

H-Tyr-Gly-Gly-Phe-Leu-OH

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