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You are in Home >> Exams >> Mitchell Anaesthetic Notes


Opioid agonists and antagonists

Created: 21/4/2006
Updated: 7/11/2006
 
a. Provide a brief overview of the history of morphine.

300 BC juice extracted from papavertum somniferum 
described by Theophratus 
contains phenanthrines and isoquinolones (noscapine, papverine)
1400s  repopularized in Europe
1806 morphine isolated by Serturner
1853  syringe invented, morphine used with ether or chloroform GA
late C19       morphine-scopolamine anaesthesia tried, high mortality 
wave of dependence/abuse

1940s         
semisynthetic opioids introduced: pethidine, methadone, nalorphine 
balanced anaethesia and neurolept anaesthesia introduced
1970s          opioid receptors differentiated


b. Explain the structure-activity relationships of the opioid agonists and
antagonists.

All L isomers
Phenolic ring, quaternary carbon, 2 more carbons, amine group
(highlighted)
4.55 Å from centre of phenol to N
Substitution of a larger group than OH at C3 reduces µ activity
Alkyl group at N produces an antagonist
Br or OH at C14 produces an antagonist

phenanthrines 
    extracted from papvertum somniferum 
    5 rings: morphine, thebaine, codeine 
    substitutions 
        3,6 diacetyl increased lipid solubility: heroin 
        3 methoxy decreased µ agonism: codeine 
        6 keto, NCH2CH=CH2, 14OH, 7-8 saturated: 
        naloxone
morphinans 
    4 rings (no ether linkage): levorphanol, 
    dextromethorphan (has NMDA antagonist activity) 
benzmorphans 
    3 rings (C6, 7 & 8 removed): pentazocine
phenylpiperidines 
    2 rings: pethidine, fentanyl, ~fentanils 
    5.66Å from ring to N 
    lipophilic chains on active N increased lipid solubility
peptides 
    endogenous opioid agonists 
    synthesized in endocrine and neural tissue 
    products all contain the same pentapeptide at the 
    N terminal which is the opioid core 
    three precursors: pro-opiomelanocortin (produces hormones: ACTH, MSH, ß-    endorphin), 
    pro-enkephalin and pro-dynorphin (produce neurotransmitters)

Figure 1: The structure of morphine

The structure of morphine

Figure 2: The structure of pethidine

The structure of pethidine

Figure 3: The structure of fentanyl

The structure of fentanyl

c. Explain the physiological nature and types of opioid receptors and the action of agonists, partial agonists, mixed agonist-antagonists and antagonists.

µ1
 
    stimulated by opiates and opioid peptides 
    µ-endorphin > dynorphin > enkephalins 
    endogenous ligand: met-enkephalin 
    exogenous agonists: morphine, fentanyl 
    G protein linked: increased K+ conductance, decreased cAMP 
    protein kinase C activation increased wind-up 
    supraspinal analgesia 
    decreased prolactin, ACTH release, increasedADH, ACh turnover, catalepsy, feeding

µ2 
    stimulated by morphine 
    G protein linked 
    respiratory depression, decreased gut motility, CVS depression (central) 
    dopamine turnover, feeding, decreased GH release

d
    stimulated by enkephalins 
    d-endorphin = enkephalins > dynorphin 
    G-protein linked increased K+ conductance decreased cAMP 
    spinal analgesia 
    GH release 
    
?1,2,3 
    stimulated by opiates and dynorphin 
    dynorphin >> ß-endorphin >> enkephalins 
    endogenous ligand: dynorphin 
    exogenous agonists: ketocyclazocine, pentazocine 
    decreased Ca2+ channel conductance

spinal analgesia
decreased?ADH, sedation, feeding
epsilon
stimulated by ß-endorphin
endocrine role, decreased?immune function

sigma
no longer classified as an opioid receptor
so-called agonists turned out to be NMDA agonists
psychotomimetic effects
morphine-3-glucuronide is an NMDA agonist
increased ?pain with high dose morphine, responsive to ketamine

mixed agonist-antagonists
nalbuphene: mu antagonist, kappa?agonist
may reverse respiratory depression without fully reversing analgesia
slow dissociating partial agonist
buprenorphine: mu partial agonist, high potency, slow dissociation

d. Explain the pharmacokinetics of the opioids and apply them to clinical useage, including infusion kinetics, transdermal, epidural, spinal and intramuscular useage.

protein binding t1/2 a
(min)
t1/2 ß
(h)
Vd
(l/kg)
Clearance 
(ml/min/kg)
pKa lipid
solubility
morphine 35% 1.65  3.0 3.2 15.0 7.9 1.4
pethidine 65% 4-11 3-8 4.4 7.5-16.0 8.7 39
fentanyl 80% 13 3.6 4.0 13.0 8.4 860
alfentanil 90% 11.6 1.6 0.86 6.4 6.5 130
sufentanil 92% 17.7 2.7 1.7 13.0 8.0 1778
remifentanil 70% 6 10min 0.35 40.0
pentazocine 60% 3.3-5.7 4.3-5.6 10.9-17.8 7.9
methadone 90%  n/a  8-36 6 ~0.5 8.6 115
codeine n/a  3  8.2
naloxone 1.5 1.0-2.5  3.6 27-35 7.9 high

Morphine is used intravenously, intramuscularly, subcutaneously, orally, intraarticular and occasionally nebulized. Its plasma levels do not correlate with clinical effect as its low lipid solubility causes slow equilibration across the blood-brain barrier. It has a high hepatic extraction ratio and so an oral bioavailability of only 30%. It is metabolized in the liver by glucuronide conjugation to morphine-3-glucuronide which is inactive and morphine-6-glucuronide which is active. These metabolites are renally cleared, so clinical effect of morphine is increased in renal failure though clearance remains constant. Metabolism is limited by hepatic blood flow.

Parenteral administration is commonly by intramuscular injection (0.1-0.2 mg/kg 3-4 hourly) or intravenous infusion for more constant plasma levels. Infusion is commonly at 1-5 mg/h in adults but a loading dose is required to achieve initial analgesia, typically 5-15 mg. Morphine is suitable for PCA. Epidural and spinal use are described but morphine is not the most suitable narcotic for this purpose as its low lipid solubility slows distribution, increasing the risk of central respiratory depression.

Pethidine is used intravenously, intramuscularly, epidurally and occasionally orally. It has an oral bioavailability of about 60%. It is metabolized in the liver to active and inactive metabolites, the most important of which is norpethidine which is a convulsant. Pethidine and its metabolites are renally cleared resulting in accumulation of metabolites in renal impairment. Its elimination half-life is prolonged in hepatic impairment.

Absorption from intramuscular injection is impaired in cold or vasoconstricted
patients. When used epidurally, pethidine crosses the dura rapidly with CSF concentration peaking at about 15 minutes at the same time as plasma concentrations. It also crosses the placenta readily and has an elimination half-life in the newborn of 24 hours.
Dosing IV and IM is similar to morphine, with pethidine being about 1/10 as potent. Epidural use is in the same dose range as IV use.

Fentanyl has a high lipid solubility and is used intravenously, epidurally and transdermally and can be used by other routes. In small doses its duration of action is determined by redistribution rather than elimination. Plasma concentrations correlate well with effect as it crosses the blood-brain barrier readily. It is metabolized in the liver by demethylation and hydroxylation to inactive metabolites which are renally cleared. A small amount may be secreted unchanged into the stomach and undergo recirculation.

Intravenous use is in two dose-ranges: 1-2 µg/kg as a coinduction or sedative agent and for brief duration analgesia and 30-100 µg/kg as an induction agent for cardiac anaesthesia alone or with N2O. In the high dose range, its elimination half-life determines the duration of action. It can be combined with droperidol in neurolept anaesthesia.

Epidural use is common either alone or with a local anaesthetic agent. The dose
range is 10-60 µg/h in adults. Fentanyl readily diffuses across the dura and also into blood.
Its high lipid solubility allows for transdermal use via patches (S-100) which deliver 50-100 µg/h. There is a long delay in reaching therapeutic plasma levels, so another analgesic is required to cover the first 6-8 hours. There is also a depot effect in the skin after a patch is removed. Use by intravenous infusion or intramuscular injection is uncommon as fentanyl is not well-suited to these uses because of its cost and short half-life.

Alfentanil is used intravenously. It is less lipid soluble than fentanyl but its low pKa results in most of the drug being in the unionized (basic) form at physiological pH, resulting in rapid diffusion across the blood-brain barrier. This, combined with a smaller Vd results in a more rapid onset of effect than fentanyl. Its elimination half-life is brief, so an infusion is required if it is to be used for anaesthesia. It is metabolized in the liver to inactive metabolites by demethylation and dealkylation.

Sufentanil is pharmacokinetically similar to fentanyl. Pentazocine is an opioid agonist(?)-partial agonist(µ). It is used IM, IV and orally. It has a high extraction ratio and a bioavailability of 20%. Its hepatic metabolism is variable from patient to patient and is sensitive to hepatic impairment, with bioavailability rising to 70%. It is rarely used.
Codeine (3-methyl morphine) is used orally for analgesia and diarrhoea. It undergoes hepatic metabolism to inactive metabolites and also to morphine. Typical doses range from 8 mg to 60 mg q4h in adults.

Methadone is used orally for chronic pain and narcotic dependence and can be used IV. Its elimination half-life is markedly prolonged in chronic oral use. It has a low clearance by hepatic metabolism and so a low extraction ratio

Buprenorphine can be used IM, IV and sublingually.
Naloxone is an opioid receptor antagonist. It is used IM and IV for narcotic overdose.
It is highly lipid soluble and has a short elimination half-life. It is metabolized in the liver by conjugation to glucuronide. Because its half-life is much shorter than most of the opioid agonists, repeat IM injection or IV infusion is required for treatment of overdose. Typical dose is 20-70 µg/kg IM or 5-10 µg/kg/h IV. Smaller doses are used to antagonize adverse effects of narcotic epidural infusions such as itch.

Naltrexone is an opioid antagonist with a lower extraction ratio than naloxone and so is used orally. It is used in an oral dose of 50 mg daily to help maintain alcohol and narcotic abstinence in dependent users who have withdrawn.

In principle, the loading dose and infusion rate of the narcotics used by IV infusion can be calculated from MEAC, Vd and clearance. In practice the dose is titrated against pain.
Loading dose = MEAC x Vd
Infusion rate = MEAC x clearance

e. Provide a detailed systematic description of the actions and pharmacodynamics of individual drugs: morphine, pethidine, pentazocine, diamorphine, methadone, fentanyl, alfentanil, sufentanil, codeine.

morphine

pharmacokinetics above
epidural, spinal use
slow distribution into spinal cord (10-15 min spinal, 15-60 min epidural)
prolonged duration due to low lipid solubility (12-20 h epidural)
late respiratory depression described
conjugated to morphine-6-glucuronide (potent analgesic)
and morphine-3-glucuronide (NMDA agonist)
also sulfated and N-demethylated
pharmacodynamics
potent µ and kappa?agonist

actions
supraspinal
cortex
anxiolysis, sedation, inhibition of REM sleep
EEG: increase in?voltage, decrease in ?frequency
mood effects: euphoria, dysphoria
stiffness
µ effect from inhibition of descending inhibitory motor pathway from caudate nucleus
brainstem
respiratory depression
decrease in CO2, O2 sensitivity (2° increase in ?ICP if hypercapnia develops)
decrease in cough reflex
CTZ: nausea, emesis

autonomic centres
increase in?vagal tone (bradycardia)
?ecrease in? sympathetic tone
analgesia
opiate receptors in periaqueductal grey, NRPG
descending inhibitory pathways in DLF

spinal
inhibit slow EPSP resulting from C fibre stimulation
most potent as preemptive analgesia
itch: from either altered threshold or direct stimulation

peripheral
analgesic activity in periphery e.g. intraarticular use

cardiovascular
direct effect on SA node to ?decrease?rate
haematological
direct effect on mast cells to degranulate and release histamine

gastrointestinal
smooth muscle spasm, damages anastomoses
decrease in?LOS tone, decrease in motility

genitourinary
? decrease in urine output (via ADH)
increase in?detrusor and sphincter tone
endocrine (? via D2 agonism)
decrease in ACTH, prolactin, GHRH
increase in ADH

clinical use
MEAC ?16 ng/ml
administered by all routes except rectal, transdermal and topical

pethidine
synthetic opioid developed as an anticholinergic (1939)
pharmacokinetics above
N-demethylated to norpethidine
50% analgesic potency, cerebral irritant
renally cleared then hydrolyzed to normeperidinic acid
t1/2ß 24 h in the neonate, fetal:maternal concentration ratio =1.0
epidural use
plasma levels peak after 10-15 min, rapid CSF penetration 15-30 min
pharmacodynamics
10% potency of morphine
µ and ?kappa?agonist
local anaesthetic, type I antidysrhythmic
anticholinergic
actions
as for morphine except:

cerebral
irritation and convulsions with accumulation of norpethidine
less miosis due to anticholinergic effect

respiratory
same reduction in ventilation, but decreased TV with little fall in rate

cardiovascular
not suitable for cardiac use because of membrane stabilizing effect
mild vasodilator

gastrointestinal
less spasm and constipation than morphine, but still ? decreased?motility

clinical use
MEAC ?0.5 µg/ml

fentanyl
synthetic phenylpiperidine-related opioid
alfentanil and sufentanil differ only in potency and pharmacokinetics

pharmacokinetics
rapid redistribution and slow elimination
high hepatic extraction ratio
metabolized by N-dealkylation and hydroxylation

pharmacodynamics
potent µ and kappa?agonist
100 times potency of morphine
actions
similar to morphine except:

cardiovascular
little effect alone, no histamine release
hypotension in large doses in conjunction with diazepam

endocrine
suppresses stress response

clinical use
MEAC 3 ng/ml
anaesthesia > 20 ng/ml
two dose ranges
coinduction 1-2 µg/kg
cardiac 30-100 µg/kg
pharmacokinetics unpredictable at intermediate doses
transdermal use occasionally
skin produces a 12-hour depot “compartment”

pentazocine
a benzmorphan
only the L-isomer is active, but it is supplied as a racemic mixture

pharmacokinetics
20% bioavailable
high extraction ratio
oxidized and glucuronidated
metabolism greatly impaired in alcoholism

pharmacodynamics
µ partial agonist, ??agonist, NMDA agonist
approximately 30% as effective as morphine as an analgesic
actions
similar to morphine except

respiratory
ceiling to µ effects: respiratory depression and supraspinal analgesia

cardiovascular
increase in?sympathetic outflow, mild increase in MAP and HR


Kindly provided by Dr James Mitchell from his pharmacology series.


ArticleDate:20060421
SiteSection: Article
 
   
    
                                            
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