Opioid Analgesics

Analgesics: Are the Drugs which selectively relieves pain by acting in the CNS or on peripheral pain mechanisms, without significantly altering the consciousness Opioids and NSAIDS Narcotics Those drugs which possess both an analgesic (pain relieving) and sedative properties.

 Opioids include natural and semisynthetic alkaloid derivatives from opium, as well as all other compounds whose opioid like actions are blocked by the nonselective opioid receptor antagonists (Naloxone). Pain: Is unpleasant sensory and emotional experience associated with actual or potential tissue damage.

Classification of Pain By Onset and Duration Acute pain

Sudden in onset Usually subsides once treated

Chronic pain
Persistent or recurring Often difficult to treat

Types of Pain contd.

Opioid Peptides
Opioids include several endogenous peptides that are synthesized by nerve cells and adrenal medullary cells and interact with opioid receptors Endogenous peptides that act on opioid receptors as endorphines, dynorphines and enkephalines. , , K and are different types of opioid receptors.

 Endogenous opioid peptides have been implicated in pain modulation.

They can be released during stressful conditions such as pain or the anticipation of pain.

Opioid Receptors
Three classes of opioid receptors ( , , ) have been identified. All are members of the G protein-coupled family.

Some opioids, can produce an agonist effect at one receptor subtype and an antagonist effect at another.
The opioids act on neurons by:
Closing voltage-gated ca2+ channels on presynaptic nerve terminals and reducing transmitter release. Hyperpolarizing and inhibiting postsynaptic neurons by opening K+ channels.

Ionic mechanism

Receptor Stimulation
mu
P hysical dependence E uphoria A nalgesia R espiratory depression

 kappa
S edation A nalgesia (spinal) M iosis

delta
analgesia

Classification of OPIOIDS
Natural morphine codeine thebaine semisynthetic heroin synthetic meperidine methadone Dextromethorphan Fentanyl pentazocin.

Classification

Strong agonists E.g.: Morphine, Methadone. Moderate agonists. E.g.: Codeine Mixed agonist-antagonist E.g.: Pentazocine Antagonists. E.g.: Naloxone

Morphine
MOA : Morphine and other opioids act through binding to opioid receptors. These receptors distributed in the CNS at regions involved in transmission and modulation of pain.

Pharmacological Actions
Strong agonist: Acute effects: 1. Analgesia: changes both pain perception and reaction to pain.
Visceral pain is relieved better than somatic pain Degree of analgesia increases with dose Nociceptive pain is better relieved than Neuropathic pain

Pharmacological Actions
2.Euphoria: Morphine produces a powerful sense of contentment and well-being

3. Sedation, drowsiness and hypnosis. Additive with other CNS depressants.

Pharmacological Actions
4.Respiratorydepression: Inhibits respiratory center and decreasing its sensitivity to CO2.
The respiratory depression is dose-related.

Death from morphine overdose is usually due to respiratory failure

Pharmacological Actions 5.Antitussive:Opioids suppress the cough reflex Produced by depression of neurons in medulla which control the cough reflex Codeine is a potent inhibitor of the cough reflex Meperidine has a weak effect

Pharmacological Actions
6.Miosis:Opioids act on and receptors to stimulate oculomotor nucleus to constrict pupil. Pin point pupils are characteristics of morphine overdose.

Pinpoint pupil

Pharmacological Actions
7. Nausea and vomiting: Stimulation of CTZ. 8. GIT effects Decreases GI motility Increases GI tone,Produces constipation . 9. Urinary retention: Due to contraction of sphincter, inhibition of reflex of urination and increase ADH.

Pharmacological Actions
10. Biliary tract: Contraction of biliary muscle and sphincter of Odi Biliary tract spasm Opioids can exacerbate biliary colic 11. Uterus: Decreases tone and prolong labor. 12. sedation& have anxiolytic effects

Pharmacological Actions 13. CARIOVASCULAR SYSTEM No prominent effects Peripheral vasodilation most prominent effect due to histamine release and decreased adrenergic tone Very high doses may produce bradycardia

 Because of respiratory depression and carbon dioxide retention, cerebral vessels dilate and increase the cerebrospinal fluid (CSF) pressure. Therefore, morphine is usually contraindicated in individuals with severe brain injury. 14. Histamine release: Morphine releases histamine from mast cells, causing urticaria, sweating, and vasodilation. Because it can cause bronchoconstriction, asthmatics should not receive the drug.

Pharmacological actions of Morphine (CNS) contd.

Depression: 1. Respiratory centre depression Both rate and depth of respiration are diminished Dangerous in Head injury and asthmatics 2. Cough Centre Depressed 3. Vasomotor centre high doses cause fall in BP

Stimulation: 1. CTZ sensitize CTZ to vestibular and other impulses 2. Edinger Westphal Nucleus miosis 3. Vagal centre Bradycardia

 Chronic effects: 1. Tolerence: Tolerance and physical dependence are manifestations of chronic toxicity Tolerance develops to: Analgesia,Euphoria,Sedation Tolerance DOES NOT develop to: Miosis,Constipation Cross tolerance develops to other opioids

2. Dependence Psychological Craving. Physical or physiological, sudden Abnormal physical state in which the drug must be administered to maintain normal function.

 Physical dependence is manifested by withdrawal symptoms when administration of the drug is stopped. Physical dependence is a powerful reinforcement for continued drug taking behavior

 Withdrawal syndrome can be induced by naloxone. Methadone : Produces very mild abstinence syndrome.

Therapeutic uses of Morphine

1. Analgesic postoperative pain Cancer pain. Renal colic. 2. Acute pulmonary edema (LVF). To decrease anxiety and pre and after loads. 3. Antitussive in severe and refractory cough. codeine has greater antitussive effect than morphine.

Therapeutic uses of Morphine

4. Preanesthetic medication. 5. treatment of diarrhea????

Contraindications
Contraindications and cautions in therapy:
Use of pure agonists with weak partial agonists. Use in patients with acute head injuries. may increase the risk of hemorrhage - respiratory depressant effect increases PCO2 cerebral VD and also morphine can increase the ICP

Use during pregnancy.

Fetal respiratory depression and withdrawal syndrome.

Impaired renal and hepatic functions. Bronchial asthma and chronic respiratory diseases. Due to : Respiratory center depression , bronchoconstriction and histamine release.

OTHER OPIOIDS
Meperidine less potent than morphine high doses produce excitation and convulsions less smooth muscle spasm and miosis, respiratory depressant effects. little antitussive action than morphine

 Uses: Analgesic as substitute of Morphine Preanaesthetic medication As analgesic during labor less fetal respiratory depression Heroin not used clinically highly addictive.

Methadone: Oral less addictive than morphine, with no or mild withdrawal syndrome. Therapeutic uses: Methadone is used as an analgesic as well as in the controlled withdrawal of dependent abusers from heroin and morphine.

Moderate agonist Codeine less potent than morphine mainly used as antitussive

 Mixed agonist antagonist and partial agonist. Drugs that stimulate one receptor but block another are termed mixed agonist-antagonists Pentazocin - - agonist and weak antagonist or partial agonist.

 ANTAGONISTS Naloxone Readily reverses the coma and respiratory depression of opioid overdose. Within 30 seconds of IV injection of naloxone, the respiratory depression and coma characteristic of high doses of heroin are reversed

Clinical Uses
Analgesia- Fentanyl, morphine Cough Supression- Codeine, Dextromethorphan. Antidiarrheal- Diphenoxylate, Loperamide Acute Pulmonary edema- Morphine Anesthesia- Fentanyl Opioid Dependence- Methadone

Tramadol
Tramadol is a strong analgesic which blocks serotonin reuptake. It is a weak receptor agonist, so can be used with full agonists for chronic neuropathic pain. It induces seizures and is relatively contraindicated in patients with a history of epilepsy.