Those drugs which possess both an analgesic (pain relieving) and sedative properties.
refer to drugs in a generic sense, natural or synthetic, with morphine- like actions
| natural |
| semisynthetic |
| synthetic |
Natural
phenanthrene
|
benzylisoquioline
|
| heroin |
| oxymorphone |
| hydromorphone |
| meperidine |
| methadone |
| morphinians |
| benzamorphans
|
Morphine
| pentacyclic alkaloid (five ring structure) |
| oxygen bridge at 4,5 position |
| three major rings (a, b, c) |
| 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) |
OPIOID receptors (located in CNS)
Receptor Stimulation
| physical dependence |
| euphoria |
| analgesia (supraspinal) |
| respiratory depression |
| sedation |
| analgesia (spinal) |
| miosis |
delta
| analgesia (spinal & supraspinal) |
| release of growth hormone |
| dysphoria (opposite of euphoria) |
| hallucination |
| respiratory and vasomotor stimulation |
| mydriasis |
OPIOID receptors
in CNS, their 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
Sigma receptor
also known as the "pcp receptor" since pcp will bind there
Mu receptor
high in areas of pain perception and at medulla (area for respiration)
Amino acid sequence of OPIOID peptides
In early 1950's, it was thought that since morphine from poppy plant had relieved pain then it was likely that their was an endogenous substance for pain relief
first found the receptor and then found the peptide which are enkephalins
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
enkephalins let a runner not feel the knee pains caused by running |
Endorphin
| 30 amino acid peptide |
| last 5 amino acids are the same sequence as enkephalins |
| endorphins are neurohormones |
| conservation between species |
| little difference in humans |
Proopomelanocortin
| various proteins that can come from this gene |
| gamma MSH, ACTH, beta LPH, alpha MSH, beta MSH, met Enk
|
| 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 (sedation) |
| 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 |
| analgesia |
| sedation |
| euphoria |
| mood change |
| mental cloudiness |
Morphine strongest analgesic today as a natural substance
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 |
| person easily go asleep, but easily aroused unlike when on barbiturates where person
goes into coma |
Morphine euphoria
| sense of well being |
| reason why morphine is abused |
Morphine given to a pain free individual
| first experience is dysphoria |
| not experienced in person in pain |
Initial Injection of opioid
makes person sick, have anxiety, apathetic, lethargic, inability to concentrate,
nausea, vomiting, and drowsiness
Morphine mood change
person who is lively will become dull when using morphine
Morphine mental cloudiness
difficulty in concentration and have apathy
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,
further respiratory depression
Morphine
CNS becomes less responsive to pCO2 thereby causing a build up of CO2
Depression on medulla affect brain center on rhythm and responsiveness gives irregular breathing patterns. As increase dose, one will see periods of apnea
Respiratory centers less responsive to pCO2 as well as medullary centers for responsiveness to CO2 in blood so irregular breathing (short breath)
normal response 2 to 3 hours after normal dose
Morphine
initially stimulates chemoreceptor trigger zone (CTZ)and then it will depress CTZ (antiemetic effect)
this may be one of the reasons for the dysphoria in pain free people
Morphine
nausea and vomiting
| morphine initially stimulates the CTZ -> emetic |
| later effect is antiemetic |
cough reflex
| antitussive effect due to direct depression of cough center in the medulla |
pupil size
| morphine produces miosis (pinpoint pupils) |
| **tolerance does not develop to miosis |
excitatory and spinal reflexes
| high doses of many OPIOID cause convulsions |
Central trigger zone
| in postrema of medulla |
| stimulation by stretch receptors causes nausea and vomiting |
| has afferents from gut and ear |
| involved in motion sickness |
Codeine in cough syrup
| it has an antitussive effect |
Morphine and all OPIOID
| they cause miosis (pinpoint pupils) |
| kappa receptor effect |
| gives indication that patient has OPIOID overdose |
| pinpoint pupils responsive to bright light |
| if block kappa receptor (causes miosis), see mydriasis from sigma effect |
| oculomotor nerve (CN3) is stimulated by kappa receptor site |
| start at edenmeyeroff nucleus. see parasympathetic discharge at oculomotor nerve giving pin point pupils |
| atropine only blocks effect indicating parasympathetics only partially explains the
miosis |
High doses (overdose situation) of morphine
| can cause convulsions |
| this is stimulation at sigma receptor |
| at really high doses, sigma receptor overwhelmed |
Summary of CNS effects of morphine
1. analgesia
| analgesia, sedation, euphoria, mood change, mental cloudiness |
2. respiration
| depression |
3. nausea and vomiting
| emetic, and antiemetic (main effect) |
4. cough reflex
| antitussive |
5. pupil size
| miosis (stimulation of cranial nerve 3) |
6. excitatory spinal reflexes
| stimulation produces convulsions (high doses) |
Cardiovascular effects of morphine lead to vasodilation
| morphine causes the release of histamine |
| suppression of central adrenergic tone |
| suppression of reflex vasoconstriction Morphine effects on the vasculature |
| morphine by itself has no direct effect on heart since no OPIOID receptor on heart, but indirectly it causes vasodilation lowering blood pressure |
| orthostatic hypotension from lying to sitting position test due to suppression of vasoconstriction reflex |
| due to less sensitivity of pCO2 in CNS, cerebral artery also dilates and have
increased intracranial pressure |
Morphine effects on the gastrointestinal system
| increase in tone and decrease in mobility leading to constipation |
| decreased concentration of HCl secretion |
| increased tone in stomach, small intestine, and large intestine |
Reason for constipation produced by morphine
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
| increases tone of smooth muscle
|
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 can prolong labor |
Morphine
| due of increased muscle tone, it gives biliary tract pain that resembles biliary colic |
| nausea |
| analgesia |
| sedation |
| respiratory depression |
| cardiovascular |
| euphoric not to: |
| miosis |
| constipation |
acute overdose
| respiratory depression |
| pinpoint pupils (miosis) |
| coma |
Treatment
1. establish adequate ventilation
2. give OPIOID antagonist (naloxone)
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 so have to reinject it
|
Therapeutic uses of morphine
| relief of pain |
| terminal illness |
| preoperative medications |
| postoperative medications |
| acute pulmonary edema |
| constipating effect |
| cough |
| obstetrical analgesia |
Morphine for relief of pain
don't give morphine for severe head injuries since it dilates cerebral blood vessels causing an increase in intracranial pressure
Morphine for terminal illness
used for the pain relief only , no effect to cure person, but makes their life tolerable with morphine
Morphine for preoperative medication
morphine alleviates some of that pain
use morphine, papaverine, fentanyl (generic name)
Fentanyl
| lasts 30 minutes |
| short duration |
| quick onset |
OPIOID give smooth induction into anesthesia
| pain relieving |
| reduces restlessness and anxiousness |
| reduces cough reflex |
| decreases pain |
| allows us to reduce amount of general anesthetic necessary
|
Disadvantage of using morphine in preoperative medications
| prolongs awakening time |
| spasms in smooth muscle |
| wheezing in asthmatic patients |
| nausea and vomiting can occur |
| constipation and urinary retention |
| hypotension due to vasodilation |
| respiratory depression |
Morphine for postoperative medication
| controls pain and discomfort after surgery |
| lets person breathe deeply |
Disadvantage of using morphine in postoperative medications
| GI effect |
| constipation |
| urinary retention |
| cough |
| cough good for clearing bronchial tree, but morphine reduces coughing |
Morphine for acute pulmonary edema with left sided heart failure
| related to anxiety level |
| high anxiety |
| not breathing well |
| pooling effect in heart |
| morphine relieves anxiety |
| breathing more deeply and pulmonary edema relieved |
Morphine for severe dysentery (ie. shigella)
| due to morphine's constipation effect |
Codeine
| drug of choice for cough |
| morphine would be too strong of a medication |
Morphine for obstetrical analgesia
| not used much since morphine crosses placental barrier |
| baby born with respiratory depression |
| meperidine is drug of choice for obstetrical analgesia |
Contraindications of morphine
| biliary colic
| ||
| acute head injuries
| ||
| asthmatics
|
**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
|
Morphine
at 3 hydroxyl and 6 hydroxyl positions have changes that change the potency and
pharmacokinetics
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 |
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 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 |
| mydriasis |
| diarrhea |
| vasoconstriction |
| dysphoria |
| etc. |
OPIOID withdrawal is NOT fatal , person won't die; but with barbiturates, withdrawal can be fatal
withdrawal from OPIOID is called going cold turkey (goose bumps on skin) and also called kicking the habit due to leg motions
as a general rule, a drug that is more potent as analgesic than morphine will have more
intense drug withdrawal symptoms
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 |
Fentanyl (sublimaze, china white)
| 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 |
| high potency |
| highly abused ,known as china white as street name |
Meperidine
| produced in 1940's
| ||
| same CNS actions as morphine | ||
| sedation, analgesia, respiratory depression | ||
| potency same as 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 |
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 |
Methadone
| pharmacological activity similar to morphine |
| long duration of activity |
| absorbed well orally |
| lasts long time |
| 16 to 20 hour duration of action |
| used in maintenance program for narcotic treatment all OPIOID are cross tolerant to each other since all act on same receptor site want to replace heroin from receptor site (short duration of action of 2 hours) with methadone (16 to 20 hour duration of action) to get people off of heroin while preventing withdrawal |
| powerful pain reliever |
| same potency as morphine
|
two drugs: naloxone 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 |
| diarrhea |
| reversible respiratory depression |
| metabolized same as morphine through glucuronic acid and excreted through kidney |
| after naloxone, when person wakes up, person will be very irritable and
agitated; after 30-45 minutes coma will return so closely supervise patients;
give another dose after drug
wears off. |
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 |
Additional Readings:
The
Use of Opioids in the treatment of chronic pain
