Opioids analgesics and antagonists By S.Bohlooli PhD

Opioids analgesics and antagonists

By

S.Bohlooli PhD

• Narcotics – Those drugs which possess both an analgesic

(pain relieving) and sedative properties. (Not Correct term)

• Opioid – refer to drugs in a generic sense, natural or

synthetic, with morphine- like actions

Classification of OPIOIDS

• Natural– phenanthrene

• morphine 10% • codeine 0.5% • thebaine 0.2%

• semisynthetic – heroin – oxymorphone – Hydromorphone

• synthetic – Phenylpiperidines (meperidine –fenatnyl)– Phenylheptylamines (methadone – levomethadyl )– morphinians (Levorphanol)– benzamorphans (pentazocine – dezocine)

• Strong agonist:– Phenanthrenes: morphine, hydromorphone, oxymorphone, heroin– Phenylheptylamines: methadone, levomethadyl– Phenylpiperidines: meperidine, fentanyl, sufentanyl, alfentanyl,

remifetanyl– Morphinans: levorphanol

• Mild to moderate agonists:– Phenanthrenes: codeine, oxycodone, dihydrocodeine,

hydrocodone– Phenylheptylamines: propexyphene– Phenylpiperidines: diphenoxylate, difenoxine, loperamide

• Mixed receptor action:– Phenanthrenes: nalbuphine, bupronorphine– Morphinans: butorphanol– Benzomorphanes: pentazocine, dezocine

• Miscellaneous:– tramadol

• Opioids antagonists:– naloxone, naltrexone, nalmefene

Classification of OPIOIDS

Chemistry

• Morphine – pentacyclic alkaloid (five ring structure) – phenolic groups (s/a hydroxyl, alcoholic, OH)

at position 3 and 6 – modifications at those positions changes

pharmacokinetics and potency of drug – nitrogen at 16 position (n16) – changing it by adding an alkyl group converts

it to naloxone (i.e. go from a agonist to an antagonist)

Morphine related opioids

Mepridine related opioids

OPIOID receptors

• CNS distribution is not uniform– they are at areas concerned with pain– receptor locations beginning with highest

concentration areas

1. cerebral cortex2. amygdala3. septum4. thalamus5. hypothalamus6. midbrain7. spinal cord

Receptor Stimulation

• mu– Physical dependence – Euphoria – Analgesia (supraspinal) – Respiratory depression

• delta – analgesia (spinal & supraspinal) – release of growth hormone

• sigma– dysphoria (opposite of euphoria) – hallucination (both visual & auditory)– respiratory and vasomotor stimulation – mydriasis

• kappa– Sedation – Analgesia (spinal) – Miosis

Opioids’ mechanism of action

Endogenous Opioid Peptides

• Three distinct families of peptides have been identified: – enkephalins– endorphins– dynorphins

• the precursors are now designated as:– proenkephalin (also proenkephalin A)– proopiomelanocortin (POMC)– prodynorphin (also proenkephalin B)

Pharmacokinetics of morphine

• absorption– readily absorbed from GI tract, nasal mucosa, lung

subcutaneous, intramuscular, and intravenous route

• distribution – Bound & free morphine accumulates in kidney, lung,

liver, and spleen – CNS is primary site of action (analgesia/sedation)

• metabolism/excretion– metabolic transformation in liver – conjugation with glucuronic acid – excreted by kidney – half life is 2.5 to 3 hours (does not persist in body

tissue) – morphine -3 -glucuronide in main excretion product – lose 90% in first day – duration of 10 mg dose is 3 to 5 hours



• Morphine administration – oral morphine not given due to erratic oral

availability – significant variable first pass effect from

person to person and have intraspecies effect (same dose will vary in person day to day)

– IV morphine acts promptly and its main effect is at the CNS


Pharmacodynamics of Morphine

• CNS is primary site of action of morphine– analgesia – sedation – euphoria – mood change – mental cloudiness


Morphine analgesia**Changes our reaction and our perception of pain • severe cancer pain is tolerated more when person is

given morphine • relieves all types of pain, but most effective against

continuous dull aching pain • sharp, stabbing, shooting pain also relieved by morphine


• Morphine sedation - morphine causes sedation effect, but no loss of consciousness

• Morphine euphoria

• sense of well being

• reason why morphine is abused

Effects of morphine on respiration

Effects of morphine on respiration

There is a primary and continuous depression of respiration related to dose – decrease rate – decrease volume – decrease tidal exchange

• mu receptor activation produces respiratory depression; with increase in dose can cause further respiratory depression

• CNS becomes less responsive to pCO2 thereby causing a build up of CO2 – rhythm and responsiveness causes irregular

breathing patterns; one will see periods of apnea


• nausea and vomiting – Stimulation of CTZ, in brain stem

• stimulation by stretch receptors causes nausea and vomiting

• has afferents from gut and ear

• involved in motion sickness



• pupil size– morphine causes miosis (pinpoint pupils) – kappa receptor effect – pinpoint pupils still responsive to bright light – oculomotor nerve (CN3) is stimulated by

kappa receptor site – if kappa receptor is blocked, mydriasis from

sigma effect will result– atropine partially blocks effect indicating

parasympathetic system involved


• Acute overdose– High doses (overdose situation) of

morphine – excitatory and spinal reflexes

• high doses of many OPIOIDs cause convulsions

– due to stimulation at sigma receptor


• Cardiovascular effects– Cardiovascular effects of morphine lead to

vasodilation, thus a decrease in blood pressure

– morphine causes the release of histamine and

– suppression of central adrenergic tone and– suppression of reflex vasoconstriction


– Morphine effects on the gastrointestinal system increase in tone and decrease in mobility leads to constipation

– decreased concentration of HCl secretion – increased tone in stomach, small intestine, and large intestine

– delay of passage of food (gastric contents) so more reabsorption of water

– **tolerance does not develop (i.e. same amount of effect each time) to this constipation effect


• Morphine effects on various smooth muscles – biliary tract

• marked increase in the pressure in the biliary tract • 10 fold increase over normal (normal is 20 mm H20 pressure) • increase due to contraction of Sphincter of Oddi

– urinary bladder • tone of detrusor muscle increased • feel urinary urgency • have urinary retention due to increased muscle tone where sphincter closed

off – bronchial muscle

• bronchoconstriction can result • **contraindicated in asthmatics, particularly before surgery

– uterus • relaxation of uterus can prolong labor


• Neuroendocrine Effects: inhibit the release of: – gonadotropin-releasing hormone (GnRH) – corticotropin-releasing factor (CRF), – luteinizing hormone (LH)– follicle-stimulating hormone (FSH)– ACTH, and - endorphin;– testosterone – cortisol.– Secretion of thyrotropin is relatively unaffected.

Tolerance to morphine

• nausea • analgesia • sedation • respiratory depression • cardiovascular • euphoric• not to:

– miosis – Constipation– Convulsive effect

Toxicity of morphine

Acute overdoserespiratory depression pinpoint pupils (miosis) coma

Treatment1. establish adequate ventilation

2. give OPIOID antagonist (naloxone)

Toxicity of morphine

Naloxone

• it has no agonist activity

• it displaces morphine from all receptors, reverses all of the effects of morphine

• its effects are immediate (3-5 min)

• duration is 30-45 minutes must be reinjected often

Therapeutic uses of morphine

• relief of pain • terminal illness • preoperative medications • postoperative medications • acute pulmonary edema • constipating effect • cough • obstetrical analgesia ?

Drug interactions with Opioids

**in general, the coadministration of CNS depressants with OPIOID often produces at least an additive depression (potentiation)

OPIOID and phenothiazines • produces an additive CNS depression as well as enhancement of

the actions of OPIOID (respiratory depression) • this combination may also produce a greater incidence of orthostatic

hypotension OPIOID and tricyclics antidepressants • can produce increased hypotension • meperidine and MOA inhibitors

– results in severe and immediate reactions that include excitation, rigidity, hypertension, and severe respiratory depression

OPIOID and barbiturates • increased clearance

morphine and amphetamine • enhanced analgesic effect

Drug interactions with Opioids

• change in the methyl group on 3 position of morphine (substituted

for the hydroxyl group) • one tenth the potency (analgesic properties) of morphine • absorbed readily from GI tract • the absorption is more regular than morphine and more predictable • given orally • metabolized like morphine through glucuronic acid • physical dependence is necessity of drug so you don't go through

withdrawal • tolerance and physical dependence is protracted from morphine

since potency of codeine is low • withdrawal from codeine is mild in relation to morphine • antitussive drug for cough

Codeine

• at 3 and 6 hydroxy positions, there are acetyl groups instead of hydroxyl groups

• it is anywhere from 3 to 4 times the analgesic potency of morphine

• heroin is the most lipophilic of all the OPIOIDs • morphine is the least lipophilic of all the OPIOID • OPIOID withdrawal is NOT fatal

Heroin (diacetylmorphine)

• When heroin is ingested, it crosses the blood brain barrier rapidly (morphine crosses slow) where it is hydrolyzed to monoacetyl morphine (acetyl group got cleaved off) and then it is hydrolyzed to morphine making more of the drug in the brain making it 3 to 4 times more potent

• withdrawal symptoms of heroin similar to morphine, but more intense (rebound effect)– mydriasis – diarrhea – vasoconstriction – dysphoria – etc.

Heroin (diacetylmorphine)

Hydromorphone• have ketone at 6 hydroxyl position of morphine • also strong agonist • 9 times more potent than morphine • more sedation than morphine so less euphoric feeling so

not abused much • less constipation • does not produce miosis • tolerance and physical dependence is more intense than

morphine because of its high potency • respiratory depression same as morphine

Hydromorphone

• synthetic drug • different structure than morphine • 80 to 100 times more potent than morphine • rapidly acting drug • used as preoperative medication • short acting (30-45 min) • onset of action is 5 minutes • very high potency • highly abused

Fentanyl

• produced in 1940's – wanted drug with less addictive liability than morphine, but it has same

addictive liability as morphine • same CNS actions as morphine • sedation, analgesia, respiratory depression • potency same as morphine • unlike morphine:• more respiratory depression • more bronchoconstriction activity • less constipation • no antitussive activity • **it causes mydriasis (not miosis) • toxic effects similar to atropine • drug absorbed orally • drug most abused by health care professionals due to its availability • withdrawal similar to morphine• Less sedative ( preferred to morphine in obstetrics)

Meperidine

• pharmacological activity similar to morphine, same potency as morphine

• long duration of activity • absorbed well orally• 16 to 20 hour duration of action• powerful pain reliever • used in maintenance program for narcotic

treatment

Methadone

• can be OTC drug now • **therapeutic use is antidiarrhea drug • meperidine type drug • has very little analgesic properties at therapeutic dose • no antitussive effect • at high doses it has analgesic effects • causes respiratory depression and euphoria at high

doses

Diphenoxylate (Lomotil)

Tramadol

• Tramadol (ULTRAM) is a synthetic codeine analog that is – a weak m-opioid receptor agonist. – Part of its analgesic effect is produced by inhibition of

uptake of norepinephrine and serotonin. – In the treatment of mild-to-moderate pain, tramadol is

as effective as morphine or meperidine. – However, for the treatment of severe or chronic pain,

tramadol is less effective. – Tramadol is as effective as meperidine in the

treatment of labor pain and may cause less neonatal respiratory depression.

Tramadol

• Tramadol is 68% bioavailable after a single oral dose and 100% available when administered intramuscularly.

• Tramadol is supplied as a racemic mixture, which is more effective than either enantiomer alone.

• The (+)-enantiomer binds to the m receptor and inhibits serotonin uptake.

• The (-)-enantiomer inhibits norepinephrine uptake and stimulates a2 adrenergic receptors.

• Analgesia begins within an hour of oral dosing and peaks within 2 to 3 hours. The duration of analgesia is about 6 hours. The maximum recommended daily dose is 400 mg.

Tramadol• Common side effects of tramadol include:

– nausea, vomiting, dizziness, dry mouth, sedation, and headache. • Respiratory depression appears to be less than with equianalgesic

doses of morphine, and the degree of constipation is less than that seen after equivalent doses of codeine

• Tramadol can cause seizures• However, the use of naloxone increases the risk of seizure.• Physical dependence on and abuse of tramadol have been

reported. • Because of its inhibitory effect on serotonin uptake, tramadol

should not be used in patients taking monoamine oxidase (MAO) inhibitors

Antagonism of Morphine

• three drugs: naloxone, nalmefene and naltrexone (pure antagonist)

Naloxone

• no analgesic activity at all • competitive antagonist at mu, kappa, and sigma receptor • displaces morphine and other OPIOID from receptor site • reverses all actions of the OPIOID and does it rather quickly • it will precipitate withdrawal • person on heroin, then naloxone will precipitate withdrawal,

but naloxone effects are seen in the first five minutes and it only lasts for 30 minutes:

• increased blood pressure • metabolized same as morphine through glucuronic acid and

excreted through kidney

Naltrexone

• same effect of naloxone except it is used orally

so can't use it if for person with acute toxicity • long duration of activity • single dose block action of heroin effects for 24

hours • once stabilized, give patient naltrexone • patient get no euphoric effect from heroin so

person gets off heroin (negative reinforcement) • approved for use by the FDA • also used for treatment of alcoholism

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Opioids analgesics and antagonists By S.Bohlooli PhD