Transcript Opioids analgesics and antagonists

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)
Classification of OPIOIDS
• 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
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 cortex
2. amygdala
3. septum
4. thalamus
5. hypothalamus
6. midbrain
7. spinal cord
Receptor Stimulation
• mu
– Physical dependence
– Euphoria
– Analgesia (supraspinal)
– Respiratory depression
• kappa
– Sedation
– Analgesia (spinal)
– Miosis
• delta
– analgesia (spinal & supraspinal)
– release of growth hormone
• sigma
– dysphoria (opposite of euphoria)
– hallucination (both visual & auditory)
– respiratory and vasomotor stimulation
– mydriasis
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)
Pharmacokinetics of morphine
• 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
Pharmacokinetics of morphine
Pharmacokinetics of morphine
• 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
Pharmacodynamics of Morphine
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
Pharmacodynamics of 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
Pharmacodynamics of Morphine
• 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
Pharmacodynamics of Morphine
• 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
Pharmacodynamics of Morphine
• 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
Pharmacodynamics of Morphine
• 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
Pharmacodynamics of Morphine
• 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
Pharmacodynamics of Morphine
– 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
Pharmacodynamics of Morphine
• 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
Pharmacodynamics of Morphine
• 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 overdose
respiratory depression
pinpoint pupils (miosis)
coma
Treatment
1. 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)
Drug interactions with Opioids
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
Codeine
• 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
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 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.
Hydromorphone
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
Fentanyl
•
•
•
•
•
•
•
•
•
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
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
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)
Methadone
• 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
Diphenoxylate (Lomotil)
•
•
•
•
•
•
•
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
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