OPIOID ANALGESICS

**counselor** Mon Oct 15, 2012 12:07 pm

OPIOID ANALGESICS

OPIUM
The name of this class of analgesic drugs derived from opium, latex condensate is collected for recording of immature capsules of Papaver somniferum.

Opium contains many alkaloids that make up about 25% by weight of opium. The most interesting alkaloid drug is morphine for its strong analgesic action. The preparation officinale "Opium powder titled" contains 10% of morphine.

The alkaloids are divided into:
fenantrenici:
morphine (9-17%), codeine (0.3-4%), thebaine (from 0.2 to 3.2%) and
benzilisochinolici:
papaverine (0.8 to 2.7%), nascapina (= 6%).

FAMILY OF PEPTIDES OPIOIDS
• Dating back to 1975, the first identification of two endogenous opioid peptides, Leu-enkephalin and Met-.
• Next was identicata the -endorphin of 31 amino acids and
• even later were discovered dynorphins.
To these peptides correspond three precursors well characterized.

More recently, other opioid peptides have been identified:
• the endomorphin, we do not know the precursor, and
• the nociceptin / orphanin FQ, which originates from pro-nocicettina/orfanina FQ.

Endorphins
Derived from the precursor pro-opiomelanocortin (POMC). In the CNS are mainly located in the hypothalamus (arcuate nucleus), pituitary and nucleus of the solitary tract in the medulla oblongata.
Originate from POMC peptides plus 20
Among them, the -endorphin, the  - and  - endorphin are all equipped with opioid activity. The -endorphin is also found in the pancreas, testis, placenta and adrenal medulla.
From POMC also originate ACTH and hormones melanocytes stimulated  -,  - and -MSH.

ENKEFALINE
Proenkefalina derived from A.
This generates, in addition to the pentapeptide Met-and Leu-enkephalin, also larger peptides.
Are widely distributed in the CNS (amygdala, hippocampus, locus coeruleus, cortex). Are also present in the adrenal medulla and in the gastrointestinal tract.

Dynorphins
Are peptides that originate from prodinorfina (or proenkefalina B).
From this arise the neoendorfina, dynorphin (1-17), dynorphin A (1- and dynorphin B (1-13).
Are widely distributed in the CNS, including the spinal cord where they are part of nociceptive sensory pathways. They localization in the CNS similar to enkefaline.

Endomorphin
Do not know the precursor molecule.
They are located in the CNS especially in areas involved in nociception (dorsal horn of the spinal cord, spinal trigeminal nucleus, amygdala, periaqueductal gray
Have analgesic action, but weak action of reinforcement.

Nociceptin or orphanin FQ
And 'present in the CNS, including the spinal cord, and in the intestine
The nociceptin / orphanin FQ represents the main peptide that is generated from the precursor.
The nociceptin / orphanin FQ presents action in some cases anti-opioid:
• blocks the rewarding effects of opioids and alcohol
• in supraspinal antagonizes the analgesic action of morphine.

Biosynthesis and metabolism
Peptides are sintetizzti in the soma and then migrate to the nerve terminal where they are stored in granules.
The fusion of the granules with the cell membrane leads to a release of the peptide in the synaptic space.
The elimination of the peptide from the synapse is not the case for reuptake, but mainly for enzymatic cleavage by of:
• aminopeptidase
• carboxypeptidase
• dipeptidylcarboxypeptidase
• dipeptidilaminopeptidasi

Physiological role
The opioid peptides control many biological functions:
• Control the pain
• Evoke rewarding effects
• Controls the respiratory function
• Controls food intake
• They are involved in the stress response
• Control the immune system
• Controls gastrointestinal function
• Controls part of the endocrine system

Opioid Receptors
4 receptor subtypes are described:
• MOP receptors that mediate:
Supraspinal and spinal analgesia,
-Euphoria
-Respiratory depression,
-Physical dependence,
Semiosis.
• KOP receptors that mediate:
-Spinal analgesia,
And sedation.
-Not suppress the withdrawal syndrome.
• DOP receptors that mediate
-Changes in affective behavior.
• Receptors NOP for the nociceptin / orphanin FQ, that block:
-Supraspinal analgesic effect of morphine
-Gratification alcohol and morphine.

Beta endorphin has affinity mainly for MOP and DOP receptors.
The enkefaline have affinity especially for DOP receptors.
The dynorphins are endogenous ligands of receptors LAD.

MORPHINE

Pharmacodynamics
The inhibitory effects of morphine are due to:
• reduction of cyclic AMP
• activation of the K + channels
• inhibition of channels for the Ca + +

Analgesia
The continuous dull pain is relieved by morphine more effectively than acute pain.
But at adequate doses also relieves the severe pain of renal origin or nature of biliary colic.

The analgesic action is quite selective:
• is not accompanied by loss of consciousness,
• to impaired motor coordination,
• emotional control and judgment.
• different from those painful sensations (touch, hearing, vision, vibration ...) are not altered.

The analgesic effect of morphine is due to:
Alteration of nociceptive-sensing mechanisms.
-Alteration of emotional reactions (anxiety, fear, panic, pain) to feel pain sensation. It is probably for this reason that patients often say that they continue to feel the pain, but tolerate it much better

a) in the spinal cord there are MOP presynaptic receptors in primary afferent fibers which is believed to decrease the release of nociceptive neurotransmitters.
b) postsynaptic receptors LAD can affect nociceptive mechanisms in the spinal cord.
c) the modulation of nociceptive activity in the spinal cord may also be due to activation of descending fibers that originate from the substance periaqueductal gray.

d) The amygdala and the locus coeruleus may be important sites of action for the effects of morphine on emotional reactions to pain.

Euphoria
Opioid drugs can induce euphoria. Heroin (especially after intravenous administration) is the drug that has more this action.
Oral administration of morphine in patients with severe pain usually does not evoke gratification and euphoria (risk of addiction <1%)

Sedation
Both in healthy subjects and in patients with pain. He warns:
-Heaviness of the extremities
-Inability to concentrate
-Decrease in physical activity.

Endocrine effects
Opiates inhibit:
-CRF, ACTH and cortisol.
-Decreased the plasma levels of GnRH, LH, FSH
-Increased secretion of prolactin and GH.
These effects correspond to physiological roles of endogenous opioids, because the naloxone determines opposite effects on the plasma concentration of these hormones.

Miosis
MOP and KOP agonists cause miosis by stimulation of the nucleus of the oculomotor nerve.

Convulsant effect
At doses higher than the analgesic opioids can cause seizures.
In some animal species (sheep, pigs, cattle, cat, horse) prevails excitement of sedation and more likely to have seizures.

Breathing
Opioids cause respiratory depression.
• Reduce the sensitivity of the respiratory centers to CO2
• Depress the pontine and medullary centers that control respiratory rhythm, up to 3-4 breaths per minute.
Perhaps the receptors which mediate respiratory depression MOP2 receptors are different from those that mediate analgesia.

Cough.
Opioids inhibit the cough for direct effect on the cough center in the medulla oblongata!

Nausea and vomiting
Are caused by morphine stimulation of the CTZ. These effects are antagonized by D2 receptor antagonists.

Cardiovascular system
-Causes arteriolar and venous dilatation, probably
mediated release of histamine.
-Inhibition of baroreceptor reflexes.
-Orthostatic hypotension
-The heart actually quite scarce.

Gastrointestinal effects
-Decreased gastric secretions, bile, pancreatic, intestinal.
-Decreases motility of the stomach and slows down considerably gastric emptying.
-Increase the intestinal tone, the amplitude of the propulsive contractions are decreased and increased the amplitude of segmental contractions not propulsive.
-Increases the tone of the ileocecal valve.
-Increases the tone of the large intestine and anal sphincter.
The constipating effect may also be due to:
-Blunting central reflex defecation.
-Actions of central origin on the control of gastrointestinal propulsive activity.

Effects on the biliary tract.
Morphine produces spasm of the lower end of the common bile duct.

Bladder
Increases the tone of the detrusor (urination), but also increases the tone of the bladder sphincter (difficulty in urination).

Uterus
Are reduced tone, frequency and amplitude of contractions. It prolongs the pains of childbirth

Skin
You have redness, due to vasodilatation. It is also noted itchy skin. Perhaps the histamine release is the basis of these skin effects.

PHARMACOKINETICS
• You have a pretty good gastrointestinal absorption, although the metabolism of the passage of the bioavailability may be 15-49%.
• Can be administered parenterally.
• Morphine is well absorbed from the nasal mucosa and lung (heroin is sniffed and smoked opium).
• The distribution in the CNS depends on the lipophilicity of the drug. Morphine is an opioid less lipophilic.
• Morphine is conjugated with glucuronic acid.
Morphine-3-glucuronide is inactive;
morphine-6-glucuronide is more active than morphine
• A small amount of morphine is excreted unchanged in the urine.

THERAPEUTIC USES
Pain Control:
The chronic use of oral morphine in patients with severe pain generates low risk of development of tolerance, physical dependence and addiction (<1%!!!).

Hypnotic and sedative effect
The use as a hypnotic is justified only by the presence of pain.
Even for sedation preanesthetic not justify opiates, if not in the presence of pain

Constipating effect
Are not used more morphine or opium for this purpose. Using loperamide and diphenoxylate to a lesser extent.

Hydromorphone, and oxymorphone
From morphine were obtained for chemical modifications hydromorphone, and oxymorphone that compared to morphine present.
• Increased lipophilicity
• Increased analgesic effect
• Lower latency effect

Methadone
Pharmacodynamics
Methadone has a complex pharmacological profile:
• stimulates receptors MOP
• E 'non-competitive antagonist of NMDA receptors
• Reduces the reuptake of serotonin
The l-methadone is 8-50 times more potent isomer d.
The racemate has analgesic activity similar to that of morphine. All other effects are very similar to those of morphine.

PHARMACOKINETICS
Good oral absorption. Has better efficacy orally than morphine.
Only a small fraction is excreted unchanged in the urine. In the liver undergoes intense biotrasfomazione
The half-life of 16-20 hours. The long half-life is related to the high volume of distribution of the drug.

TOXICITY
As for morphine. In acute attention to the longer duration of action.

Tolerance and Dependence
It develops tolerance and dependence as for morphine.

THERAPEUTIC USE
Methadone is used:
• As an analgesic (can work even in the case of neuropathic pain because of its NMDA receptor antagonism)
• In the treatment of opiate withdrawal syndrome. In the weaning of heroin addicts.

Buprenorphine
Pharmacodynamics
• E 'MOP receptor partial agonist and DOP
• E 'receptor antagonist LAD
• E 'agonism at NOP
- It produces analgesia similar to morphine.
- As a partial agonist may precipitate a withdrawal syndrome in heroin addicts under the influence of relevant doses of heroin, but
- Suppress the same syndrome in addicted subjects, deprived of the drug.
- Summons lower intestinal effects compared to morphine
The effects of buprenorphine is more difficult to antagonize with naloxone

THERAPEUTIC USE
Buprenorphine is used:
• As an analgesic
• In the weaning of heroin addicts

Meperidine
Pharmacodynamics
• Has an analgesic potency 7-10 times lower than morphine.
• Meperidine depresses respiration as morphine equianalgesic doses.
• Unlike morphine, meperidine has not constipating effect.

PHARMACOKINETICS
Good oral absorption. Approximately 50% of drug is subject to metabolism The passage. Orally superior efficacy to morphine.
Is eliminated metabolically especially in the liver.

TOXICITY '
Such as morphine, except for the lower incidence of constipation and urinary retention.
It may have high incidence of phenomena of excitation (convulsions) caused by normeperidine, which has half-life of 15-20 hours and can give accumulation.

THERAPEUTIC USE
E 'used as an analgesic for acute treatments. It has the advantage of efficacy for oral and minor intestinal problems.
E 'used as an analgesic during labor. A equianalgesic doses compared to morphine and methadone gives less respiratory depression in the fetus.

And fentanyl congeners
Fentanyl is about 80-100 times more potent than morphine as an analgesic.
He half-life of 20-30 min. Its effects on respiration are short-lived.
Alfentanil and sulfentanil have longer half-lives.
Remifentanil has an extremely short half-life (2-3 min) from the time that is cleaved by esterases in plasma and tissue.
They are used as analgesics, but also for surgeries (neuroleptanalgesia / anesthesia)

Opioids WEAK

Codeine
Has analgesic potency approximately 10 times less than that of morphine.
It 'metabolized by CYP2D6. Among its metabolites is morphine-6-glucuronide.
It may be a prodrug of morphine, since subjects with deficiency of the enzyme respond poorly to codeine.
It 'liable to abuse
From codeine were obtained synthetic compounds such as oxycodone and the idrossicodone

THERAPEUTIC USES
Is used as an antitussive and analgesic as weak.

Tramadol
• In addition to opioid action
• Blocks the reuptake of serotonin and noradrenaline
• It has analgesic activity 10 times lower than that of morphine
Has superior bioavailability to that of morphine after oral administration
The metabolite or-desmethyltramadol is more active than the same tramadol.

THERAPEUTIC USES
It is used as an analgesic weak.

Dextropropoxyphene
Has an analgesic potency equal to 1/2, 2/3 compared to codeine.
Respiratory depression goes hand in hand.
Has low Charges of abuse.

THERAPEUTIC USE
Weak analgesic in combination with NSAIDs

Opioid use for gastrointestinal
Loperamide
It has a powerful constipating effect
Is not well absorbed orally and not well exceeds the blood brain barrier for which very little has central effects.

Diphenoxylate
Exerts a powerful constipating effect. At the doses used for this purpose is very poor with morphine. Going with the doses, however, have effects typical of opioids.

Opioid Antagonists

Naloxone and naltrexone
Pharmacodynamics
Naloxone and naltrexone are competitive antagonists of the receptors MOP, DOP and KOP. They have no residual agonist activity.

• They have little effect in patients not taking opioids
• They reduce the pain tolerance
• antagonize the analgesia by acupuncture
• antagonize analgesia by stress
• attenuate hypotension in case of shock (hypovolemic or endotoxin)
• attenuate food intake by stress
• Repairs levels of FSH and LH in women stressed

In patients who have taken an overdose of opiates are increasing respiratory rate (depressed) in 1-2 min. Blood pressure returns to normal.

In heroin addicts antagonists precipitate withdrawal syndrome, which appears in a few minutes and disappears after about 2 hours.

PHARMACOKINETICS
Naloxone is administered parenterally.
Has a duration of action of 1-4 hours.
For oral administration has a strong metabolism of the passage.
Naltrexone is more potent than naloxone and has greater effectiveness orally.
Has a longer duration of action ( 24 hours).

THERAPEUTIC USES
• Acute poisoning by opiates
(Naloxone is used because it has the shortest half-life, of
result is less than the risk of precipitating a
withdrawal syndrome if the person is addicted to heroin)
• Diagnosis of physical dependence to opiates (using naloxone).
• Treatment of alcoholic subjects (in the U.S. has approved the use of naltrexone)
• Prevention of relapse in heroin addicts after weaning dependence (naltrexone is used for longer duration of action).

ABUSE OF OPIOID

Can be recognized modes of abuse of opiates:
-Abuse of opiates in a pain relief, or to suppress the cough
-Stimulant use (usually heroin).
-Abuse of methadone or buprenorphine used in drug addict to replace heroin.

At the base of the abuse is the search euphoric effect of opiates. The compound is preferred by addicts heroin because:
• Gives greater rewarding effect
• Summon minor side effects such as nausea, itching and bronchospasm

The biggest impact could be rewarding due to:
• Maggire both lipophilic and therefore greater distribution in the CNS
• both high affinity for the receptor hypothesized for morphine-6-glucuronide. Moreover, the heroine also generate large quantities of this glucuronide.

TOLERANCE:
Tolerance develops especially for:
• depressing effect on breathing
• analgesic effect
• euphoric.
• Instead istaura not sensitive to the tolerance effect miotic and constipating.

PHYSICAL DEPENDENCE
The establishment of addiction can be very rapid. After 2-3 days of intake, naloxone produces withdrawal symptoms.
Dependence is observed in all the ANS and CNS.
At the base of physical dependence is a controadattamento the actions of drugs.
This produces "latent hyperexcitability" that originates rebound phenomena to the suspension of the drug.
Perhaps the physical addiction to opiates can be linked to adaptation of cAMP inhibitory effect of morphine.

SYNDROME OF ABSTINENCE
The heroin withdrawal syndrome occurs after about 8-12 hours after the last dose and reaches a maximum after about 70 hours. Disappears after 5-10 days.
Mostly observed hyperexcitability bounce:
-Restless sleep and restless
-CNS hyperexcitability (ejaculation and orgasm)
-Strong craving for opioid
-Lacrimation, sweating, runny nose
Mydriasis-
-Diarrhea, vomiting, abdominal cramps
High-pressure and heart rate
-Increased response to CO2

The withdrawal syndrome from methadone:
-It occurs more slowly
-E 'less intense
-It lasts longer (up to 3 weeks)
Drugs with short damage symptoms more intense, but of shorter duration.
The withdrawal syndrome from heroin does not put the person in danger of life, the danger occurs instead in the newborn employee.

Weaning DA OPIOIDS

The replacement of methadone is a standard technique of weaning opiate used for at least forty years.
A daily dose of 40 mg should be sufficient to prevent the appearance of withdrawal syndrome.
Generally one operates daily reduction of methadone order of 5% of the daily dose.
A serious risk that the subject is now weaned take heroin again to usual doses that could result in overdose.

More recently it has been adopted the use of buprenorphine, a partial agonist of MOP receptors.
Buprenorphine can, as a partial agonist, also to reduce the rewarding effects of heroin, may be summarized.

It 'also practiced the technique of using the administration of clonidine or lofexidine even better (which has fewer cardiovascular effects). There are two  2 adrenergic agonist that reduce neuronal hyperactivity with decreased vegetative symptoms and anxiety. But do not suppress effectively the craving for the drug opium.

Naltrexone may be useful after weaning for the maintenance of the free drug in the subject; subject treated with naltrexone reinstatement of heroin does not evoke the expected effects and does not remount the behavior of compulsive abuse.
Naltrexone is preferred to naloxone as orally active and long duration of action.

In weaning you draw on methods of behavior modification.
-Hospitalization
-Psychotherapy
-Therapeutic Communities

Dangers of
• infections (septicemia, hepatitis, endocarditis, AIDS)
• Emboli from foreign bodies
• Injuries neurological and musculoskeletal contaminants
• Increased suicidal tendency
• Increased criminal activity to procure the drug
• High mortality rate (approximately 15 times higher than non-drug users)
• Problems related to acute intoxication and chronic

ACUTE POISONING BY OPIOIDS
It can be caused by:
Accidental Overdose in-addicts
-Suicide attempts
Overdose-clinical
In a normal subject can be lethal for doses above 30 mg to about 120 mg parenterally or orally.

Signs and symptoms
• For high doses of the drug you have a deep coma.
• The pupils are pinpoint. Only belatedly, as a result of hypoxia, can be dilated.
• There is respiratory depression, up to 2-4 cycles per minute.
• The decrease of breathing down your blood pressure. If hypoxia persists it comes to damage to capillaries and then to circulatory shock.
• It has been frequently pulmonary edema.
• The body temperature is lowered.
• Death is usually due to respiratory failure.

Therapy
• Ensure the airway.
• Ensure ventilation of the patient.
• Administer naloxone intravenously, 0.4 mg / time, repeat the treatment at intervals of about 3 min. A total dose of 10 mg should be effective.
• Naltrexone, a long-acting antagonist, may trigger withdrawal symptoms.

INTOXICATION CHRONIC OPIOIDS
• Digestive disorders (nausea, vomiting, constipation alternating with bouts of diarrhea)
• Miosis
• Weight Loss
• Anemia and cachexia
• Sexual impotence in men
• Amenorrhea in women
• Irritability, suspiciousness, loss of moral sense forms hallucinatory and maniacal.