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OPIOID AGONISTS AND ANTAGONISTS

Prof. Dr. Shah Murad

shahmurad655@yahoo.com

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Narcotics Those drugs which possess both an analgesic (pain relieving) and sedative properties.

Opioid refer to drugs in a generic sense, natural or synthetic, with morphine- like actions

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Classification of OPIOIDS

Natural phenanthrene

morphine 10% codeine 0.5% thebaine 0.2%

semisynthetic heroin oxymorphone Hydromorphone

synthetic meperidine methadone morphinians benzamorphans

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Chemistry

Morphine pentacyclic alkaloid (five ring structure) oxygen bridge at 4,5 position three major rings (a, b, c) phenolic groups ( 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)

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Receptor Stimulation

muP hysical dependence E uphoria A nalgesia (supraspinal) R espiratory depression

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kappaS edation A nalgesia (spinal) M iosis

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delta analgesia (spinal & supraspinal) release of growth hormone   

sigmadysphoria (opposite of euphoria) hallucination (both visual & auditory) respiratory and vasomotor stimulation mydriasis

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OPIOID receptors

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

concentration areas 1. cerebral cortex 2. amygdala 3. septum 4. thalamus 5. hypothalamus 6. midbrain 7. spinal cord

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Endogenous Opioid Peptides

Three distinct families of peptides have been identified: the enkephalins, the endorphins, and the dynorphins. Each family is derived from a distinct precursor polypeptide

These precursors are now designated as proenkephalin (also proenkephalin A), proopiomelanocortin (POMC), and prodynorphin (also proenkephalin B)

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Endogenous Opioid Peptides

Enkephalins they are 5 amino acids long also have met enkephalin (methionine at 5' position)

and leu enkephalin (leucine at 5' position) enkephalins are neuromodulators

since they are small peptides, it was found that they came from larger peptides (pro enkephalins) proenkephalin gene codes for peptide 276 amino acid in length

cleavage of proenkephalin gives 4 to 5 pieces of activated enkephalins

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Endorphin POMC (proopiomelanocortin) is processed into

melanocyte-stimulating hormone (g-MSH), adrenocorticotropin (ACTH), and b-lipotropin (b-LPH); within the 91-amino-acid sequence of b-LPH are found b- endorphin and b-MSH

30 amino acid peptide last 5 amino acids are the same sequence as

enkephalins endorphins are neurohormones conservation between species little difference in humans

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Prodynorphin yields more than seven peptides that contain leu-enkephalin, including dynorphin A(1-17), which can be cleaved further to dynorphin A(1-8), dynorphin B(1-13), and a- and b-neoendorphin, which differ from each other by only one amino acid.

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Pharmacokinetics

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)

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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 is main excretion

product lose 90% in first day duration of 10 mg dose is 3 to 5 hours

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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

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CNS is primary site of action of morphine

analgesia sedation euphoria mood change mental cloudiness

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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 given to a pain free individual first experience is dysphoric not experienced in person not in pain

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

Morphine euphoria sense of well being reason why morphine is abused

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Effects of morphine on respiration

There is a primary and continuous depression of respiration related to dose

decrease rate decrease volume decrease tidal exchange

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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

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nausea and vomiting – Stimuation of CTZ, in area postrema of medulla

stimulation by stretch receptors causes nausea and vomiting

has afferents from gut and ear involved in motion sickness

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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 if kappa receptor is blocked, mydriasis

from sigma effect will resultatropine partially blocks effect indicating

parasympathetic system involved

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Acute overdose

High doses (overdose situation) of morphine

excitatory and spinal reflexes high doses of many OPIOID cause

convulsions due to stimulation at sigma receptor

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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

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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

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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 contraction of uterus

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Neuroendocrine Effects

inhibit the release of gonadotropin-releasing hormone (GnRH) and corticotropin-releasing factor (CRF), thus decreasing circulating concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), ACTH, and b- endorphin; the last two peptides are usually released simultaneously from corticotrophs in the pituitary.

As a result of the decreased concentrations of pituitary trophic hormones, the concentrations of testosterone and cortisol in plasma decline. Secretion of thyrotropin is relatively unaffected.

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Tolerance to morphine

nausea analgesia sedation respiratory depression         cardiovascular euphoric not to:

miosis constipation

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Toxicity of morphine

acute overdoserespiratory depression pinpoint pupils (miosis) coma

Treatment1. establish adequate ventilation2. give OPIOID antagonist (naloxone)

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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

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Therapeutic uses of morphine

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

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Drug interactions with Opioids

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

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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 MAO inhibitors >>>>>>>>>> results in severe and immediate reactions that include

excitation, rigidity, hypertension, and severe respiratory depression

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OPIOID and barbiturates increased clearance

morphine and amphetamine enhanced analgesic effect

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Codeine change in the methyl group on 3 position (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

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Heroin (diacetylmorphine) 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 OPIOID morphine is the least lipophilic of all the

OPIOID OPIOID withdrawal is NOT fatal

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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.

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Hydromorphone (trade name is dilaudid) 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

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Fentanyl (Sublimaze) 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 ,known as china white as street name

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Meperidine 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

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unlike morphine: more respiratory depression more bronchoconstriction activity less constipation no antitussive activity **it causes mydriasis (not miosis) toxic effects similar to atropine

dry as a bone, blind as a bat, red as a beet, mad as a hatter have dry mouth

drug absorbed orally drug most abused by health care professionlas due to its

availability withdrawal similar to morphine

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Methadone pharmacological activity similar to morphine,

same potency as morphine long duration of activity absorbed well orally16 to 20 hour duration of actionpowerful pain reliever used in maintenance program for narcotic

treatment

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Diphenoxylate (Lomotil) can be OTC drug now **therapeutic use is antidiarrhea drug (treats diarrhea) meperidine type drug has very little analgesic properties at therapeutic dose no antitussive effect at high doses it has analgesic problems causes respiratory depression and euphoria at high

doses

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Antagonism of Morphine

two drugs: naloxone and naltrexone (pure antagonist)

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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

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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 used for emergency treatment 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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Non-Steroidal Anti-inflammatory drugs (NSAIDs)

Analgesic, Anti-pyretic and Anti-inflammatory drugs OR Non-narcotic analgesics or non-

opioid analgesics)

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differ from opioid analgesics in several respects.

Effective only in superficial pain of somatic origin but not of deep visceral origin.

Effective in pain of low to moderate intensity. Cause respiratory depression only in very

high doses. Have no abuse liability.

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CLASSIFICATION

Analgesics and Anti-inflammatorySalicylatesAspirin

Salicylamide Benorylate Diflunisal

Pyrazolone derivativesPhenylbutazone

Oxyphenbutazone

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Indole derivatives Indomethacin Sulindac

Propionic acid derivatives Ibuprofen Ketoprofen Naproxen

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Anthranilic acid derivatives Mefenamic acid

Aryl-acetic acid derivatives Diclofenac Tolmetin

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Oxicam derivatives Piroxicam Tenoxicam Meloxicam

Pyrrolo-pyrrole derivatives Ketorolac

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Sulfonanilide derivatives Nimesulide

Alkanones Nabumetone

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Analgesic but poor anti-inflammatory

Para-aminophenol derivatives Paracetamol (acetaminophen)

Pyrozolone derivatives Metimazol (Dipyrone) Propiphenazone

Benzoxazocine derivatives Nefopam

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Beneficial actions due to inhibition of PG synthesis

Analgesia – prevention of pain nerve ending sensitization

Anti-pyresisAnti-inflammatoryAnti-thromboticClosure of ductus arteriosus

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Shared toxicities due to inhibition of PG synthesis

Gastric mucosal damage Bleeding due to inhibition of platelet functionLimitation of renal blood flow: Na+ and water

retentionDelay / prolongation of labourAsthma and anaphylactoid reaction in

susceptible individuals

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Uses

As analgesic. Headache, toothache, myalgia.

An antipyretic. Effective in fever of any origin.

Acute rheumatic fever. Dose 4-6g/day Rheumatoid arthritis. Dose 3-5g/day Osteoarthritis

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Post myocardial infarction and post stroke patients. Aspirin inhibits TXA2 synthesis in platelets.

Pregnancy induced hypertension and pre-eclampsia – imbalance between TXA2 and PGI2.

Patent ductus arteriosis. Aspirin can bring about closure