OPIOID ANALGESICS AND ANTAGONISTS

Department of Pharmacology

Medical School Padjadjaran University

OPIOIDS are natural or synthetic compounds produce morphine – like effects

Opiates are drugs obtained from the juice of opium poppy

Action : Binding to specific receptors in the CNS effect that mimic the action of endogenous pepetide neurotransmitters (= opiopeptines) e.g. enkephalins and endorphin

Many other effects

Primary use Relief intense pain and its anxiety

Euphoric properties DRUG ABUSE

OPIOID RESEPTORS

1. On the membranes of certain cells in the CNS

2. On nerve terminals in the periphery

3. On the cells of the GIT

The terms of the receptors :

Mu, kappa, delta and sigma each exhibits a different specificity

Mu and kappa analgesics properties

Enkephalins more selectively interact with delta receptors in the periphery

Sigma receptors less specific can also bind non opioid agents (hallucinogen) Sigma is responsible for the associated effects with opioids e.i hallucination and dysphoria

Naloxone is an antagonist to mu, kappa, delata but not to sigma

All opioid receptors :

1. Coupled to inhibitory G protein

2. Inhibit adenyl cyclase

3. Associated with ion channels to

increase K+ efflux hyperpolarization

or reduce Ca++ influx impeding

neuronal firing and transmitter

release

Opioid agonists and antagonists are :

1. STRONG AGONISTS : morphine, meperidine, methadone, fentanyl-sufentanil,heroin

2. MODERATE AGONISTS : propoxyphen, codeine

3. MIXED AGONISTS-ANTAGONISTS : pentazocine, buprenorphine

4. ANTAGONISTS : naloxone, naltrexone

Actions of agonists and antagonists at opioid receptors

Mor, Her, Cod, Fent Pentazocine

Mainly at mu recept. Agonist at kappa

Partial antagonist at mu

+ - + +

Mu Kappa Sigma

Antagonists act at mu, kappa, sigma receptors

Action of drugs :

At Mu receptors : 1. Suprapinal analgesia

2. Respiratory depression

3. Euphoria / sedation

4. Physical dependence

5. Decreased GIT motility

6. Pupil constriction

Kappa receptors :

1. Spinal analgesia

2. Sedation/dysphoria

3. Pupil constriction

Sigma receptors :

1. Dysphoria

2. Hallucination

3. Psychomimetic effects

4. Pupil dilatation

Distribution of opioid receptors :

1. Brainstem : Resp., cough, nausea, vomit, BP, pupil, stomach secretions

2. Medial thalamus : deep pain that is poorly localized and emotionnaly influenced

3. Spinal cord on substantia gelatinosa : sensory information, painful afferent stimuli decrease

4. Hypothalamus : affect neuroendocrine secretion

Distribution of opioid receptors (cont.)

5. Limbic system :concentrate in amygdala,

influence emotional behaviour

6. Periphery : inhibit Ca++ dependent release of

excitatory pro inflammatory substance (e.g

Substance P) from these nerve endings

7. Immuno cells : the role has not been determined

Morphine

Crude opium contains major analgesic morphine and lower concentration of codein

Both have high affinity to Mu, varying to Kappa and Delta and low to Sigma receptors

The prototype agonist

Mechanism of action :

Interacting with opioid receptors in CNS and GIT :

Hyper polarization of nerve cells

Inhibition of nerve firing

Presynaptic inhibition of Transmitter release

Acts at Mu receptor in substantia gelatinosa

Spinal Cord

Decrease substance P in SC

Mechanism of action (cont.)

Inhibits the release of any excitatory trnsmitters from nerve terminals carrying nociceptive (painful) stimuli

ACTION of morphine

1. Analgesia result of raising threshold at SC level and altering the brain’s perception of pain (aware the presence of pain but the sensation is not unpleasant

2. Respiration : reduction of sensitivity of neurons in Resp. center to CO2 respiratory depression (with ordinary dose). Higher dose cause respiratory cease, if dose more higher (OD) death.

3. Depression of cough reflex. Morphine and codeine are antitussive. The receptor is defferent than those involved in analgesia.

4. Miosis result from stimuli of Mu and Kappa receptors. Morphine excites the Edinger-Westfal of acculomotor nerve enhanced stimuli of parasympathic nerve to the eyes.

All addicts pinpoint pupil specific

Emesis caused by stimulating the CTZ ; this symptom is not unpleasant

GIT : mophine relief diarrhea and dysentery

smoot muscle : motility , tone

Billiary tract Pressure

Anal sphincter tone constipation

Cardiovascular, very high dose gives effects hypotension, bradycardia

Respiratory depression + CO2 retention cerebral vessels dilates pressure of CSF

Morphine is contraindicated in severe brain injury

Histamine release : urticaria, sweating, vasodilatation, bronchodilatation (Asthmatics is CI)

Hormonal actions :

Inhibits releas of GTHR, CTRH

Decreases the concentration of LH, FSH,

ACTH, FSH, beta endorphine

Decreases Testosteron and Cortison

Increases Prolactin and GH

Increase ADH urinary retention

THERAPEUTIC USES

As an analgesia. When pain is present and needed sleep, morphine is supplements to benzodiazepin to induce sleeping.

Antidiarrhea