Pharmacology Opioids

 

Opioid Agonists and Antagonists MORPHINE AND RELATED OPIOIDS History first undisputed reference to "poppy juice" is found in the writings of Theophrastus in the third century B.C. the word opium being derived from the Greek word for "juice" the drug being obtained from the juice of the poppy Papaver sominiferum Arabian physicians were well versed in its uses and introduced the plant to the Orient Paracelsus, circa 1500, is credited with repopularising the drug in Europe, where it had fallen out of favor due to toxicity in the 18th century opium smoking became popular in the Orient and its ready availability in Europe led to considerable abuse opium contains more than 20 alkaloids and in 1806, Sertürner isolated a pure substance in opium, which he named morphine, after Morpheus, the Greek Gre ek god of dreams isolation of other alkaloids soon followed, codeine in 1832 and p  pa apaveri ne in 1848 th  by the middle middle of the 19  century, use of the pure alkaloids rather than crude opium was becoming widespread the problems of widespread addiction led to the search for a morphine morphine antagonist, and in 1951 nalorphine was used in the R X of morphine overdose at the same time, the analgesic effects stimulated including , pentazocine, butorphanol etc. the development of a number of new drugs, naloxone  by 1967, researchers had concluded concluded that that the complex complex interactions interactions and differences differences between morphine and its derivatives could only be explained by the existence of more than one receptor  type   → receptor dualism, Martin (1967) in 1973, following an approach developed by Goldstein, 3 groups of workers described saturable, stereospecific binding sites for opiate drugs in 1975, the enkephalin pentapeptides were isolated from pig brain since then researchers have shown that there are three distinct families of endo ndoggenous opi opioi oid  d   peptides and multipl multiplee categories of opioid receptors

N atural Al Alkalo kaloii ds o off Op O pi um

Classification

 phenanthrenes  phenan threnes

morphin morphine, e, codeine, thebaine thebaine

 benzylisoq  benzy lisoquin uinolin olines es

papaverine, papaverine, noscapine noscapine

 Sem  Se mi-sy i- synt nthe hettic D eri vati ves

diacetylmorphine (heroin) hydromorphone, oxymorphone hydrocodone, oxycodone

 Syntthe  Syn hettic D eri vati ves  phenylp  phen ylpiperi iperidin dines es

pethidine, pethidine, fentany fentanyl, l, alfentany alfentanyl, l, sufentny sufentnyll

 benzmorphan  benzm orphanss

pentazocine, pentazocine, phenazocine, phenazocine, cyclazocin cyclazocinee

 propionani  propio nanilides lides

methadone methadone

morphinans

levorphanol

 

Opioid Agonists and Antagonists Structure Activity Relationship detailed analysis of opioid stereospecificity has led to a hypothetical three dimensional model of  the opiate receptor  the majority of compounds exist as complex structures, usually with a number of optical isomers, of which only the l-isomer  is  is usually active the structural simmilarities within most in this class include, a.  b.

stru struct ctu ure con confor orm ms tto o a "T"T-sh shap ape" e" a tertiary, positively positively charged charged basic nitrogen

c.

a quaternary carbon, C13 in morphine,

d.

i.

separa separated ted fr from om the the basi basicc nit nitro roge gen n by an ethan ethanee (-C (-CH H2--CH2-) chain

ii.

attach attached ed to a phe pheny nyll gr grou oup p (p (phe heno nol, l, keton ketone) e)

the the presenc presencee of an an aroma aromatic tic rin ring, g, who whose se centre centre is is 0.455 0.455 nm from from the the nitr nitrog ogen en atom atom

short chain alkyl group substitution at the basic nitrogen results in agents with mixed agonist-antagonist agonist-antago nist actions additional hydroxylation at C14 results in an antagonist  agent  agent  phenylalanin  pheny lalaninee and tyrosine form form important important structural elements elements of the endogenous endogenous opioids opioids

Opioid Receptors following their description in 1973, and that of the endogenous opioids in 1975, a large amount of data was collected this provided a degree of contradictory information which could only be explained by the  presence of a number number of opioid receptors the evidence for the existence of multiple opioid receptors includes, a.

diff differe erent nt fa fam milie iliess of of opio opioid idss disp displa lay y diff differe erent nt p  pha harma rmaccologi logiccal profile rofiless

 b. c.

they display display different different r ank orde orderr of po pote tenci ncie es in different bioassays the app appar arent ent K d ' for na nalo loxone xone differs in the same bioassay with different agonists

d.

necess arily occur  cross tolerance does not necessarily

e.

agon agonist istss display display diff differe erent ntial ial resp respon onses ses after after alky alkyla lati tion on of of recept receptor or sites sites

f.

the rank order of di  varies according to the opioid already bound displaceme splacement nt pote potency  ncy  varies to the receptor 

further, the concentration and proportion of receptor subclasses changes with time and under the influence influ ence of an ag oni nist st d drr ug

2

 

Opioid Agonists and Antagonists except for some types of σ-receptors, naloxone binds with high affinity affinity to all opioid receptors however, its affinity for µ-receptors is generally ~ 10 fold greater  the discovery of δ-receptors was essentially the result of work with met- & leu-enkephalin leu-enkephalin however, since no exogenous opioid has the same spectrum of activity as either of these substances, the knowledge of pharmacological effects of their stimulation is lacking therefore, the actions of opioids are generally described with reference to only 3 types of  receptors   →

µ, κ , & σ

on the basis of these receptors, rece ptors, drugs can be divided divided into four groups, a.

agonists

 b.

antagonists antagonists

c.

agonist-antagonists

d.

partial aag gonists

Agent Class

Example

Action

 A  Ag gonist

morphine fentanyl  pethidine  pethid ine

activation of all receptor subclasses, though, with different affinities

Antagonist

naloxone

devoid of activity at all receptor classes

Agonist-Antagonist

nalorphine  pentazocine

agonist activity at one type and antagonist activity at another 

Partial Agonist

buprenorphine

activity at one or more, but not all receptor types

with regard to pa  partia rtiall agonist gonistss, receptor theory states that drugs have two independent  properties at receptor sites, a.

affinity  the ability, or avidity to bind to the receptor   proportional to the association rate constant, Ka

 b.

efficacy  or, i ntr ntr i nsic a act ctii vity , and is the ability of the D-R complex to initiate a  pharmacologi  pharm acological cal effect

3

 

Opioid Agonists and Antagonists drugs that produce a less than maximal response and, therefore, have a low intrinsic activity are called pa  partia rtiall agonist gonistss these drugs display certain pharmacological features, a.

the slo dose-res ponse curve is less than that of a full agonist agonist  slope of the dose-response

 b.

the dose response curve curve exhibits exhibits a ceiling with the maximal response below that obtainable by a full agonist

c.

part artial ag agonist stss ar are ab able tto o antagonise the effects of large doses of full agonists

Characteristics of Opioid Receptors Receptor

Tissue Bioassay

Agonists

mu1

guinea pig ileum

morphine

mu2

delta

guinea pig ileum

 phenylp  phen ylpiperi iperidin dines es

analgesia  bradycardia  brady cardia sedation

morphine

respiratory depression

 phenylp  phen ylpiperi iperidin dines es

euphoria  physical dependen  physical dependence ce

  δ-Ala-δ-Leu-Enk 

mouse vas deferens

"DADLE"

kappa

ketocyclazocine

rabbit vas deferens

dynorphin nalbuphine  butorphanol

 SK F -10 -10,04 ,047  7 

sigma

 pentazocine

epsilon

rat vas deferens

 

Major Actions

β-endorphin

4

analgesia-weak  respiratory depression analgesia-weak  respiratory depression sedation dysphoria -delerium hallucinations tachycardia hypertension stress response acupuncture

 

Opioid Agonists and Antagonists

Receptor Characteristi Characteristics cs mu

delta

 

µ1

spinal & supraspinal analgesia euphoria  physical  phy sical dependence dependence catalepsy miosis hypothermia  prolactin release inhibition of testosterone

µ2

respiratory depression morphine induced bradycardia inhibition of GIT motility

δ

spinal analgesia dependence without drug seeking behaviour  stress-induced analgesia endotoxic shock  hypotension hyperthermia GH release spinal analgesia sedation respiratory depression miosis diuresis dysphoria

kappa

 

κ 

sigma

 

σ

dysphoria hallucinations respiratory and vasomotor stimulation stimulation mydriasis

ε

stress response acupuncture

epsilon

 

5

 

Opioid Agonists and Antagonists Endogenous Opioid Peptides first described by Hughes et al . in 1975 three distinct families of peptides have since been identified, 1.

the enkephalins   →

met-ENK & leu-ENK 

2.

the endorphins   →

β-END, α-END & γ -END -END

3.

the dynorphins   →

DYN-A, DYN-B, α-neodynorphin & β-neodynorphin

each of these families is synthesised from a genetically distinct precursor polyeptide, which has a characteristic distribution within the body these are designated, a.

proenkephalin

or proenkephalin-A

 b.

pro-opiomelanocortin pro-opiomelanocortin POMC

c.

prodynorphin

or proenkephalin-B

each of these contains a number of polypeptides, (see G&G fig. 22-1) POMC is cleaved to ACTH and β-lipotropin (LPH) β-LPH has no opioid activity but is cleaved to β-endorphin in spite of their differences, all of the three families of endogenous opioids possess the common amino-acid sequence,

Tyr - G ly - Gly G ly - Phe P he the highest concentrations of β -endorphin occur in the pituitary gland and in the basal, medial, and arcuate regions of the hypothalamus there are some long axoned neurons which synapse in the septum, periaqueductal grey and thalamic regions of the midbrain it is unclear whether β-endorphin exists functionally in the spinal cord it does exist outside the CNS, in the placenta, small intestine, and in the plasma  by contrast, the enkephalins are widely distributed throughout throughout the CNS, a.

lim limbic bic syst system em (am (amygd gdal aloi oid d & sept septal al nu nuclei clei))

 b.

medial medial thalam thalamic ic nuclei nuclei

c.

periaq periaque uedu ductal ctal grey grey matt matter er & midl midlin inee reticul reticular ar form formati ation on in in the the midbr midbrain ain

d.

th thee peri periv ven entr tric icul ular ar gre grey y are areas as in in the the med edu ulla lla

e.

lamin laminae ae I, I, II & IV IV of of tthe he spi spina nall ccord ord (substa (substant ntia ia ge gelat latin inosa) osa)

f.

the ar area po postrema (C (CTZ)

NB: all of which are involved in the reception of affer ent noc nocii cept ceptii ve information dynorphin is found in the hypothalamoneurohypophyseal axis but its function here is unclear  it also is found in areas relevant to nociception, the limbic system, periaqueductal grey, thalamus, and laminae I & V of the dorsal horns

6

 

Opioid Agonists and Antagonists Mechanisms and Sites of Opioid-Induced Analgesia opioids do not alter the threshold or responsiveness of afferent nerve endings, endings, or the transmission along peripheral nerve fibres they may decrease conduction within primary afferent fibres entering the spinal cord opioid binding sites ( µ-rec  µ-receptors) are located on the terminal axons of primary afferents within laminae I & II (substantia gelatinosa) of the spinal cord, and in the spinal nucleus of the trigeminal nerve here they decrease the p  re lease of neurotransmitters, neurotransmitters, predominantly predominantly su  pre resy syna nap pti c  release  sub bsta stanc nce eP  interneurones in the dorsal horn are predominantly inhibitory to the soma of  enkephalinergic  interneurones cells in the deeper laminae IV & V morphinee is inactive at these sites, at which met-ENK, morphin met-ENK, a δ-receptor agonist inhibits inhibits neuronal firing

NB: in the spinal cord both µ & δreceptors are responsible for the inhibition of pain stimulation of pain fibres activates enkephalinergic neurones in the spinal cord, which play a role in the "gating" of pain and in mediating the effect of de desce scendi nding ng me medullar dullaryy analg analge esic si c pat pathwa hways ys  further modulation of nociception involves the periventricular and periaqueductal grey matter  direct microinjections of morphine, or electrical stimulation produce analgesia which can be  blocked by by naloxon naloxonee stimulation at this level results in barrages of impulses travelling in descending pathways to the dorsal horns of the spinal cord from these areas pathways bridge the medullary nuclei to the hypothalamus, amygdala and cortex there is also a lso a high concentration or receptors in, a.

the the cau caudal dal spi spinal tr triigemi eminal nucleu cleuss which receives input from the face and hands via branches of the 5th, 7th, 9th and 10th cranial nerves

 b.

the solitary nuclei nuclei which receive visceral input from the 9th & 10th cranial nerves and the area postrema

in man, the distribution of endogenous opioids does not parallel the distribution of opioid receptors, except for kappa receptors & dynorphin dynorphin the main mechanism underlying opioid action is the stimulation of stereospecific receptors, on or  near Na+-channels, which results in a de decr crea eased  sed  sod  sodi um cond nduc ucttanc nce e in active membranes in addition, they may result in, a.

a local local an anaes aesth thet etic ic act actio ion n, whic which h iiss not not stere stereos ospe peci cifi ficc

 b.

increased gK  gK + & gCa++, with membrane hyperpolarization

c.

an eff effec ectt at GABA rec ecep epttors

there appear to be additional, non-opioid nociceptive modulatory systems in the CNS  pathways are involved in the modulation of opioid induced analgesia  serot  se roto one nerg rgic  ic  pathways -adrenergicc agonists such as clonidine have additive/synergistic effects α-adrenergi

7

 

Opioid Agonists and Antagonists tolerance appears to result from uncoupling  of the usual drug-receptor effect this is likely achieved by, 1.

a decrease in the number  of  of receptors

2.

a reduction of their affinity  for  for a given agonist, and

3.

a su subcellular uncoupling  of the receptor and second se cond messenger 

there is little cross-tolerance between different receptor groups the high affini affinity ty agonists, ie. those with the greatest receptor re ceptor reserve, are least prone to produce tolerance differing receptor affinities also explains the disparity between the duration of clinical effect for  some agents and their plasma clearances radioligand-receptor studies have shown a marked and widespread reduction in mu and delta receptor densities with age this is a specific effect, as similar studies show an increase in benzodiazepine receptors the cardiovascular   system system also possesses opioid receptors, being located in, a.

the heart

 b.

branches of the cardiac vagus vagus & sympathetic sympathetic nerves nerves

c.

the the medu medulllary lary car cardi dioo-re reg gulator atory y cen centr tres es

d.

the adrenal medulla

Othe Ot herr CN CNS S E ffe ff ect ctss EEG changes shift toward low frequency, high voltage patterns and may result in decreases in REM sleep two of the most important excitatory  effects  effects include, a.

nausea & vomiting

 b.

miosis miosis

 N&V is due to direct stimulation stimulation of the the CTZ in the area postrema of the medulla this is also stimulated by apomorphine, a dopaminergic  agonist  agonist some relief from the N&V of morphine is afforded by the phenothiazines which posses a dominant dopamine-blocking action  N&V is relatively uncommon uncommon in recumbent recumbent patients but occurs occurs in 15-40% of ambulatory ambulatory patients patients therefore there may be a vestibular  component   component miosis is caused by most mu & kappa receptor agonists due to stimulation of the Edinger-Westphal nucleus  pinp  pinpo oi nt pup upii ls being pathognomic of opioid poisoning

8

 

Opioid Agonists and Antagonists they generally decrease the responsiveness of the hypothalamus, causing, a.

lowered ered body tem temper erat atu ure

 b.

decreased release of GnRH   →

lowered FSH, LH, ACTH & β-END

c.

increased GH & prolactin

?? decreased dopaminergic inhibition

d.

po possi ssibl bly y ch chan ang ges in ADH ADH secre secreti tion on (d (dis ispu puted ted))

 Muscle  Musc le R i gid gi di ty  high doses may produce muscular rigidity, characterised by increasing muscle tone progressing to severe stiffness, particularly in the thoracic and abdominal muscles the influence of dose and rate of injection has not been formally examined, but there appears to  be a higher higher incidence incidence with with large large boluses and rapid rapid infusio infusions ns (RDM) the incidence is also higher in the elderly  and  and with the concomitant use of N 2O the highest incidence appears to be with alfentanyl it may occasionally occur upon emergence from anaesthesia and very rarely several hours after  the last dose the occurrence of delayed rigidity may related to delayed, or second plasma peaks of fentanyl there is one report in a neonate whose mother received fentanyl abnormal muscle movements, from extreme flexion to global tonic-clonic activity, may occur  whether these movements related to subcortical seizure activity is unknown the effect is probably central, rigidity being blocked by neuromuscular paralysis and there being no associated rise in serum creatinine kinase, suggesting there is little muscle damage the effect may be due to action on opioid receptors, plus dopaminergic & GABA'ergic interneurones, in the substantia nigra and striatum recent evidence implicates the nucl nucle eus rrap aphe he p pontis ontis as an integral central site in opioid rigidity

Effects of Opioid Induced Muscle Rigidity Pulmonary

decreased compliance decreased FRC decreased VM hypercarbia hypoxaemia

Cardiovascular

increased CVP & PAP increased PVR 

Other Effects

increased ICP increased MRO2 dislodgement of lines raised plasma fentanyl levels

 pretreatment with, or the concomitant use of the nondepolarising muscle relaxants significantly reduces the severity and incidence the severity may be reduced by the use of the be benzodi nzodiaze azepi pines nes, though, this is contested

9

 

Opioid Agonists and Antagonists C er ebr al B loo lood dF Flow  low  the opioids generally produce produce a modest (~ 10-15%) de decr crea ease se in CMRO2 and ICP in contrast to the volatile agents they are cerebral vasoconstrictors this occurs even in the presence of nitrous oxide Guy Ludbrook thinks they uncouple CBF & CMRO2

morphine (1-3 mg/kg + 70% N 2O) causes insignificant changes in CBF and CMRO2   fent  fe nta any nyll (100 µg/kg + 70% N2O) causes dose related de decr crea eases ses in, a.

CBF

to a maximum of 50%

 b.

CMRO2

to a maximum of 35%

similar changes are observed with sufentanyl and alfentanyl all of these agents decrease CS CSF F form forma ati on while not affecting reabsorption therefore, some recommend their use in neuroanaesthesia

NB: however, alfentanyl and sufentanyl may increase ICP in patients with brain tumours, whereas fentanyl does not ! tumours, the reason for this difference is unknown

T he herr mor egulat gulatii on & Shi ver ver i ng the volatile agents decrease the thermoregulatory thermoregulatory threshold threshold by ~ 2.5 °C evidence eviden ce is scanty s canty but it appears that N2O/fentanyl results in a similar decrease, to ~ 34.5 °C shivering is common during recovery but its occurrence in relation to anaesthesia is inconsistent and incompletely understood it does however result in an increased minute ventilation, MRO2, and cardiac output, with a decrease in the mixed venous PvO2  pe  pethid hidine ine is unique among the opioids, in that 25-50 mg/70 kg, effectively terminates or  attenuates shivering in 70-80% of patients  pethidine  pethi dine is is also effective effective epidurally   when when shivering occurs after epidural administration of local anaesthetic

NB: morphine and fentanyl are ineffective

10

 

Opioid Agonists and Antagonists OPIOID ANAESTHESIA there is still considerable debate as to whether opioids in their own right produce anaesthesia to date there is no study  showing  showing that opioids alone, without muscle muscle relaxants or other  supplementation, will reliably produce anaesthesia in humans most studies assess the reductions in volatile MAC in animal models, demonstrating a ceiling effect which is subanaesthetic the problems with these studies include, a. the the prof profil ilee of action action of th thee opio opioid idss vari varies es consi consider derabl ably y wit with h ani anima mall spe speci cie es, thus extrapolation to humans is not readily achieved  b.

as inhibiti inhibition on of mo motor tor r esp esponses onses occur at deeper levels of anaesthesia than unconsciousness, amnesia and analgesia, methods metho ds requiring motor motor responses, eg. tail clamp studies, underestimate underestimate effect e ffect

c.

the volat volatile ile agen agents ts inhi inhibit bit descen descendin ding g inhi inhibit bitory ory pain pathway pathwayss activated activated by the opio opioids, ids, therefore may decrease the effectiveness of the opioids

however, the presumed specific action of the opioids would not be expected to produce anaesthesia others have postulated that the analgesia produced at subanaesthetic concentrations and the unconsciousness produced at higher levels may be mediated by different processes this dua duall me mechani chanism sm hypothesis requires that in addition to the receptor mediated effects, an opioid must be lipid soluble enough to act as a general anaesthetic supporting this, this, a biphasic response has been noted with both fentanyl and sufentanyl

Awareness Under General Anaesthesia following the introduction of ether, this only again became a problem with the introduction of the muscle relaxants and the concept of "balanced anaesthesia" the most practical definition of awareness, is "the spontaneous recall of events oc occurrin curring g under  general anaesthesia" the key point is recall should be sp  spo onta ntane neo ous many studies have shown the persistence of auditory evoked potentials under general anaesthesia and there have been many studies on word/picture recognition awareness has been reported with many anaesthetic techniques and whether the use of opioid anaesthesia is associated with an increased incidence is debated reported incidences vary from 1-25%, though, a level of ~ 1-2% is generally considered accurate there are a number of factors which influence the likelihood of anaesthesia being produced with opioid alone, a.

age

 b.

pre-existing pre-existing disease disease states

c.

patient habit

d.

acute tto olerance

- smoking, alcohol

although pa  pain does not often accompany awareness, a national inquiry in the UK revealed an incidence of pain in ~ 41% of cases of awareness 11

 

Opioid Agonists and Antagonists unconscious following following a dose of  age is a major factor, the percentage of patients rendered unconscious fentanyl 30 µg/kg being, a.

18-39 yrs

~ 57 %

 b.

31-45 yrs

~ 77 %

c.

46-60 yrs

~ 53 %

d.

> 60 yr yrs

~ 100 %

the detection of awareness is clinically difficult and usually limited to the possibility with increased autonomic activity  during  during light anaesthesia tearing, sweating, tachycardia, pupillary dilatation, salivation, eyelid or head motion, and increased spontaneous respiratory effect are considered signs of too light anaesthesia the addition of supplemental hypnotic/sedative drugs decreases the likelihood of awareness, however they do not guarantee this and they frequently prolong prolong postoperative sedation and a nd respiratory depression the addition of 0.3-0.6 MAC of a volatile agent will usually ensure amnesia but frequently compromises the cardiovascular stability sought by an opioid based technique

Cardiovascular System  Morph  Mo rphii ne morphine & related opioids produce minimal effects in normal supine subjects however they do produce, a.

peri eripher eral al vas ascu cullar dilati ation

 b.

reduced peripheral peripheral resistance

c.

depr depres essi sion on of the the bar baror orec ecep epto torr rref efle lex xes  

→

 p  po ost stura urall hy hyp potens nsion ion in erect subjects

these effects are produced by a number of mechanisms, a.

release of histamine

 b.

a direct centrally mediated mediated reduction in sym sympathetic pathetic tone tone - reversed by naloxone naloxone

c.

a vag agal al induced ced bra rad dycar cardia dia

d.

direct and indirect (PaCO2) mediated vasodilatation

e.

spl splanch anchn nic se sequ ques estr trat atio ion n of bloo blood d

although hypotension, hypertension, bradycardia and numerous other problems have been reported following morphine administration, these appear less frequent  with  with fentanyl administration of 1.0 mg/kg slowly over 5-10 minutes usually does not  result  result in significant changes in supine patients

12

 

Opioid Agonists and Antagonists the effects of morphine on the myocardium are not significant in normal man in patients with IHD, morphine reduces myocardial VO2, LVED pressure & work, therefore, it is acceptable for cardiac surgery c.f. the inhalational agents in patients with aortic valvular disease CO & SV may actually be increased Vasko et al . have demonstrated a positive inotropic effect in dogs, which is dependent upon release of endogenous catecholamines catecholami cate cholamine ne rrele elease ase has been shown to parallel histamine release in patients with cardiac disease this effect is less pronounced with fentanyl and alfentanyl most of the opioids decrease decreas e the ratio of sympathetic / parasympathetic tone when admin administered istered as a bolus bolus dose if not counteracted by the release of endogenous endogenous catecholami ca techolamines, nes, or the administration administration of agents which modify the autonomic response, they may result in profound hypotension  patients dependent upon upon a hig high h level of sympathetic sympathetic tone, or on exogenous exogenous catecholamines, catecholamines, are extremely subject to hypotension caution should be used in patients with a reduced circulating blood volume, or especially cor  res ulted  p  pulm ulmo ona nale le where sudden death has resulted the concurrent use of phenothiazines may exaccerbate morphine induced hypotension

hypertension during cardiovascular surgery has also been a problem with all of the opioids, morphine included morphine the postulated mechanisms include, light or inadequate anaesthesia, reflex mechanisms, activation of the renin-angiotensin system, and sympathoadrenal activation with the exception of pethidine, all µ-receptor agonists are associated with de decr crea eases ses in HR  factors associated with an increased risk of bradycardia, or asystole as ystole on anaesthetic induction induction with opioids, a.

treatment with Ca++-channel -channel,, or β-adrenergi -adrenergicc blockers

 b.

concomitant concomitant use of benzodiazepin benzodiazepines es

c.

muscle re relaxants wi with minimal vagolytic pr properties

- ve vecuronium

d.

muscle relaxants with vagotonic properties

- succinylcholine

e.

added vagal stimuli

- laryngoscopy

f.

rapi rapid d adm admiinist stra rati tion on of the the opi opioi oid d

13

 

Opioid Agonists and Antagonists F enta ntanyl nyl fentanyl in analgesic (2-10 µg/kg), or anaesthetic (30-100 µg/kg) doses seldom causes significant decreases in blood pressure when given alone, even in patients with poor LV function this may be due to its lack of effect on plasma histamine levels virtually all CVS parameters remain significantly unchanged   after anaesthetic doses of fentanyl this is even less than that seen with sufentanyl or alfentanyl, thus fentanyl may be the choice of  agent in patients with poor LV function in contrast, most data suggests that alfentanyl is associated with more hypotension, bradycardia and surgically induced hypertension, than either fentanyl or sufentanyl hypotension following fentanyl is mostly due to bradycardia and can be prevented by the use of  anticholinergics, sympathomimetics or agents such as pancuronium this is more likely to occur in patients with high pre-existing sympathetic tone animal studies with effective autonomic paralysis confirm that the cardiac effect are almost certainly indirect 

hypertension is the commonest disturbance with high dose fentanyl anaesthesia, usually accompanying intubation, accompanying intubation, sternotomy, or aortic a ortic root dissection this may be managed by increasing the dosage, however, this may result in unduly prolonged respiratory depression the total dose is often limited limited to ≤ 100 µg/kg and haemodynamic control achieved by the use of, a.

su supp ppllemen ementa tall volati atile ag agent ent

 b.

supplemental supplemental intravenous intravenous agent

c.

vasodilator th therapy

 Sufent  Sufe nta any nyll is ~ 5-10x as potent as fentanyl and causes hypote hypotensi nsi on with equal or greater frequency as it is presented in the same sa me concentration concentration as fentanyl, there is greater propensity for overdosage it does not increase the plasma histamine level but does induce a vagally mediated bradycardia as for fentanyl, the CVS effects are centr centrally ally med medii ate ated  d  there is a greater degree of myocardial myocardial depression and hypotension, hypotension, however, this is associated with a better attenuated response to intubation a number of studies suggest that sufentanyl is a more "complete" anaesthetic cf. fentanyl, and there is less need to use supplemental agents

 Alfe  Alf ent nta any nyll alfentanyl is an extremely short acting agent, which is ~ 1/5 to 1/3 as potent as fentanyl moderate doses result in minimal cardiovascular change and it shares most of the cardiovascular   properties of fentany fentanyll and sufentany sufentanyll at comparable comparable doses very large doses (5 mg/kg) mg/kg) are associated with increases in HR, CO, PVR, and SVR  other studies have found transient increases with moderate doses (200 µg/kg) it is the least reliable in blocking hypertensive responses during surgery thus it is unlikely to replace fentanyl or sufentanyl in cardiac anaesthesia

14

 

Opioid Agonists and Antagonists Myocardial Ischaemia & Coronary Blood Flow the opioids do not  protect  protect against coronary ischaemia in animal models whereas some protection may be offered by the volatile agents also, the opioids are less effective in blunting the hypertensive responses during surgery other studies have found that the opioids maintain the MRO 2/CBF ratio, as well or better bette r than the volatile agents  hascoronary been associated with a higher   incidence  incidence ofthe myocardial alfentanyl ischaemia, as indicated by reversal of the and decreases the LVED compliance lactate gradient frequently haemodynamic parameters are stable and do not  reliably  reliably indicate ischaemia Slogoff et al . compared sufentanyl versus the halothane, enflurane and isoflurane for CABG surgery and found no difference in, a.

peri periop oper erat atiive my myocar ocardi dial al isc isch haem aemia

 b.

postoperative MI, or 

c.

death

this occurred despite, a.

vo vola lati tile le in indu duced ced hy hypot poten ensio sion n was do doub uble le su sufe fent ntan anyl yl

 b.

sufentanyl sufentanyl hypertensio hypertension n was double double that of the volatiles volatiles

NB: tachycardia was the only variable significantly associated with ischaemia and it occurred with equal frequency in all groups the opioids have no significant effect on coronary vasomotion and do not interfere with autoregulation or the coronary response to drugs this significantly contrasts the volatile agents which are coronary vasodilators

Opioid Supplements the rational for the use of adjuvants to the opioids is, a.

red edu uce the incid cidence of awa awarr eness

 b.

control hypertension

c.

decrease subsequent r esp spii r ator tor y depression

nitrous oxide is the most common supplement to high dose opioid anaesthesia alone it has minimal cardiovascular effects, mildly depressing cardiac contractility in humans however, in association with the opioids, N2O results in significant cardiovascular depression these changes occur with all of the opioids in virtually all studies a lower FIO2 may be in part responsible myocardial ischaemia may occur and increases in systemic vascular resistance may contribute to the reduction in cardiac output this later aspect may mask myocardial depression by maintaining arterial pressure

15

 

Opioid Agonists and Antagonists i nhala nhalati tio onal ag ents similarly depress the myocardium, however, tend to do so in a more  predictable and dose dependent  predictable dependent fashion their addition allows a continued high FIO2 and will control haemodynamic responses when opioids alone are insufficient low concentrations of isoflurane have been used successfully during sufentanyl anaesthesia however, undesirable cardiovascular depression can occur during supplementation with these agents, especially halothane an undesirable redistribution of coronary blood flow may occur with both isoflurane and enflurane even so, the ease of addition and titration of these agents makes them useful adjuvants

benzodi be nzodiaze azepi pines nes produce minimal cardiovascular disturbance when administered alone this, plus their amnesic  qualities  qualities make them a desirable supplement to the opioids they are synergistic and decrease the quantity of opioid required for "anaesthesia" however, when combined with the opioids they frequently result in significant cardiovascular 

depr de pressi ession on some studies have suggested that lorazepam & fentanyl may produce less depression than other  combinations most studies indicate that benzodiazepines, even as premedication, cause significant reductions in CI, HR, BP, and SVR  the mechanism is probably centrally mediated other adjuvants include, 1.   β -blockers i.

reduc reducee opio opioid id requ requir irem emen ents ts and and th thee need need fo forr supp supple lem men ents ts

ii.

impr improv ovee haem haemod ody ynamic amic stab stabiility ity

iii. iii.

decrease the intra/p intra/postop ostoperati erative ve incid incidence ence of myocard myocardial ial ischaem ischaemia ia

iv.

de decr creas easee the the inci incide den nce of dy dysr srhy hyth thm mia iass

2.   α2-agonists have been studied little to date clonidine has been evaluated as a premedicant, where it, i.

redu reduce cess an anae aest sth heti etic rreq equ uirem rements ents

ii.

all allows ear earllier ex extu tub bati ation

iii.

lowe lowerr plasm plasmaa catech catechol olam amin inee lev levels els

iv.

less shivering

v.

3.

?d dec ecre reas asiing SNS SNS ou outf tflo low w & noc ociice cept ptio ion n

higher ca cardiac ou outputs respiratory function is well preserved when morphine 0.2 mg/kg + clonidine 0.2-0.4 mg is administered as premedication

Ca++-entry blocker blockerss (CEB) can significantly depress contractility  when  when combined with the volatile agents opioid / CEB interactions appear to be mild to moderate the presence of other agents and state of LV function function appear to be more important important

16

 

Opioid Agonists and Antagonists Respiratory System all µ-re respiration,  µ-recceptor a ago gonist  nist  cause a dose dependent depression of respiration, 1.

redu reducti ction on in th thee brai brains nstem tem sensi sensiti tivi vity ty to CO2 decrease in the slope of the CO2-ventilation response curve

2.

increase in the ap apnoe noeii c thre thr eshold 

3.

decrease the hyp hypo oxi c dr dr i ve to respiration carotid body chemoreception is virtually abolished by analgesia doses of opioids

4.

depression depression of pontin pontinee & medul medullary lary centres centres inv involv olved ed in in rhy rhythm thmic ic respir respiratio ation n

  however affect hypoxic pulmonary vasoconstriction NB: they do not  however high concentrations concentrations of opioid receptors are located in the nucleus tractus solitariu s olitarius, s, nucleus nucleus retroambigularis and nucleus ambiguus, all of which are intimately involved in respiratory regulation respiratory depression may be governed by a separate group of receptors, µ 2 c.f. the µ1-receptors involved in analgesia (G&G, RDM)  initially the respiratory rate is affected more than tidal volume, but as the dose is increased all  phases of respiration respiration are depressed  both natural natural sleep and the opioids opioids relatively spare the diaphragmatic diaphragmatic component component of respiration, respiration, impairing predominantly pre dominantly tho thorr acic excursi xcur sio on even small analgesic doses markedly accentuate the normal right-shift of the CO2-ventilation curve seen in normal sleep the cough reflex is also depressed by a central mechanism all of the respiratory effects are greater in the elderly  (  (≥ 60 yrs) the immature BBB of neonates allows greater penetration of morphine, usually excluded due to its low lipid solubility this difference is not seen with the highly lipid soluble agents the respiratory depressant effects are potentiated by any oth other er CNS depressant depressa nt drugs, especially the volatile agents, alcohol, the benzodiazepines and barbiturates

NB: exceptions to this rule are sc  sco opola lam mine & drop rope eri dol morphine is dangerous in patients with respiratory insufficiency and should be used cautiously in asthmatics as asthmatics a s large doses may produce produce bronchospasm fentanyl has antimuscarinic, antihistaminergic and antiserotonergic actions, and is therefore superior to morphine in asthmatic patients respiratory depression following fe  fent nta any nyll outlasts its analgesic effects ~ 2x (60 vs. 20-30 min) studies have found respiratory depression up to 5 hrs after induction with fentanyl 10 µg/kg recovery from the ventilatory effects of fentanyl closely parallel blood levels, cf. morphine where depression persists despite falling plasma levels with induction doses of fentanyl (50-100 µg/kg) depression may persist and require ventilatory support for 12-18 hours  pharmacokineti  pharm acokineticc data predict and clinical clinical studi studies es have confirm confirmed ed that both alfentan alfentanyl yl and sufentanyl allow more rapid recovery of respiratory function than fentanyl the respiratory pharmacodynamic effects of alfentanyl and sufentanyl are indistinguishable from those of fentanyl

17

 

Opioid Agonists and Antagonists delaye de layed d rre espi spirr at atory ory de depressi pression on has been reported with most of the opioids, including morphine,  pethidine, fentany  pethidine, fentanyl, l, alfentanyl alfentanyl,, and sufentany sufentanyll the exact cause of this phenomenon is unclear and may result from, a.

seco secon ndary dary plas asm ma drug rug peak eaks sequestration of ~ 20% of fentanyl in the stomach large peripheral storage compartments compartments (skeletal muscle) muscle)

 b. c.

supplemental supplemental analgesics analgesics and other other medications medications lack ack of of no nocice cicept ptiive sti stimulati ation

Factors Increasing Opioid Respiratory Depression Increasing dose Intermittent bolus vs. continuous infusion Increased brain penetration, or drug delivery delivery decreased distribution, distribution, low CO increased increase d unionised fraction (respiratory (respira tory alkalosis) Decreased reuptake from the brain (respiratory alkalosis) Decreased drug clearance decreased liver blood flow (abdominal surgery) intrinsic liver disease Secondary plasma drug peaks  peripheral storage compartments, compartments, lung, lung, fat, muscle muscle sequestration in the stomach Increased ionised ionised fraction at the the receptor site (respiratory acidosis) Sleep Increasing age (≥ 60 yrs) and neonates Metabolic alkalosis

18

 

Opioid Agonists and Antagonists Gastrointestinal Tract the use of opium for the relief of diarrhoea preceded its use for analgesia by many centuries the effects seen in man (species differ markedly) include, a.

so som me decre ecreas ased ed HCl se secr cret etiion

 b.

decreased gastric motility motility & increased increased antral tone

c. d.

de decr creas eased ed to tone ne of th thee low lower er oe oeso soph phag ageal eal sphi sphin ncter  cter  st increased tone in in the 1  part of the duodenum

→

delayed ga  gast stri ri c emptyi ng & delayed dr ug ab abso sorr pti tion on

e.

bili biliar ary y & pa pan ncr crea eati ticc sec secre reti tion onss are are de decr crea eased sed

f.

in incr creas eased ed re resti stin ng to tone ne & peri period odic ic sp spasm asmss of of th thee SI SI

g.

increas ased ed amplitude of of non-propulsive contractions

h.

propu propulsi lsive ve cont contrac ractio tions ns are are marke markedl dly y decrea decreased sed,, especial especially ly prox proxim imal al++

i.

wate ater rrea eab bsor sorption is is in incr creeas aseed   ≡  increased increase d transit time

 j.

viscosity viscosity of chyme chyme is increased increased

k. l.

increa crease sed d ton tonee of of th the il ileo-c eo-cec ecal al valv alve propu propulsi lsive ve contra contracti ction onss of of the the LI LI are are dim dimin inish ished ed ± abo aboli lishe shed d

m.

restin resting g ton tonee in the the LI LI is is increa increased sed to to the the poin pointt of spasm spasm

  ≡  water reabsorption

these effects are mediated by central (vagal) and peripheral (myenteric opioid and cholinergic receptor) mechanisms even in small doses, opioids decrease the release of ACh from p  terminals in the GIT  pre resy syna nap ptic  terminals thus, large doses of atropine may partly reverse the effects of morphine resection of the extrinsic nerve supply or ganglionic blockade do not do so  and a marked increase all opioids cause a dose related increase in tone of the sp  sphinc hinctter o off Od Odd di  and in biliary tract pressure ( ≤ 10x) the of athis effectexacerbation is closely parallels plasma opioid levels this duration may cause marked of biliary colic, or result in severe epi g astr str i c pa paii n which may be confused with biliary or cardiac disease most studies suggest the mixed agonist-antagonist agonist-antagonist agents produce less of an effect the increases in biliary pressure are, with the exception of that caused by pethidine, reversed by

naloxone  gluca  gluc agon gon, 1-3 mg carefully titrated may also relieve opioid induced biliary spasm fentanyl increases intestinal blood flow, and decreases MRO2, in a dose dependent manner  thus it may increase mesenteric portal PvO 2 and hepatic oxygenation the opioids result in mild decrease in liver function, similar to that caused by the volatile agents

19

 

Opioid Agonists and Antagonists Genitourinary System morphine has significant ADH properties, which may be due to CNS release release of ADH only occurs under unusual circumstances, eg. vomiting or surgical stimulation in lightly anaesthetised patients antidiuresis after morphine administration has been attributed to decreases in RBF and GFR  studies comparing postoperative urine function in volatile versus high dose opioid anaesthesia show no significant difference, unless the dose of morphine is sufficient to decrease mean arterial  pressure kap appa pa agoni agonists sts result in a free water diuresis by either decreasing the secretion of ADH, or  altering the distal tubular response most available data suggests these effect for fentanyl, alfentanyl, and sufentanyl are clinically insignificant ureteric tone and peristalsis are increased tone of the detrusor muscle is increased, as is the tone of the internal urethral sphincter  sphincter 

→

urinary retention & urgency

large doses may prolong prolong labour and restore normal tone in an oxytocic excited uterus, however  the mechanism is unclear 

Endocrine System Effects Def'n: " stre  stress ss re resp spo ons nse e" the overall normal metabolic response to surgery, characterised by hypermetabolism and mobilisation of energy stores  plasma concentration concentrationss of most stress hormones hormones increase with g general eneral anaesthesia and are increased further with surgical stimulation these increases are presumed to be undesirable as they promote cardiovascular instability intraoperatively intraoperativ ely and in the t he postoperative period the exact nature of these responses depends upon a number number of factors, factors , including, including, a.

affe affere rent nt ne nerv rvee ffun unct ctio ion n fro from m th thee affe affect cted ed area area

 b.

pain

c.

hypo pov volaem aemia and and hae haem mor orrh rhag agee

d.

arter arteria iall pH, pH, hy hypo poxi xia, a, tem tempe pera ratu ture re ch chan ange gess

e.

CNS injury

f.

starvation

g.

drugs

h.

immune status

20

 

Opioid Agonists and Antagonists despite the variability of the stimulus, the body has a number of common responses to an insult, these include, a.

pituitary trophic ho hormones

- ACTH, GH, ADH - prolactin, endorphin

 b.

catabolic hormones hormones

- cortisol, catecholamines catecholamines - thyroxine - glucagon

and testosterone, are NB: in addition, plasma levels of the anabolic hormones, insulin and usually de decr crea eased  sed  the opioids are effective in reducing these responses, however, the precise mechanism is unclear  they are capable of reducing nociceptive input and altering neuroendocrine responses there are a number of different hypothalamic opioid receptors and the endogenous opioids appear to act themselves themselves as stress s tress hormones hormones the greatest evidence for this is the cosynthesis of β -endorphin and ACTH within POMC while morphine inhibits the pituitary-adrenal response to stress, it increases some of the stress related hormones hormones levels of plasma catecholamines increase, probably due to, a.

histamine release

 b.

direct adrenal adrenal release

c.

rele release ase fr from om sy sym mpa path theti eticc ne nerv rvee en endi din ngs

 fent  fe nta any nyll and its cogners appear to be more effective than morphine in modifying the stress response fentanyl is more effective than halothane in abolishing the rise in cortisol and GH seen with surgery except during CAB G surge urgery  ry , fentanyl more effectively attenuates the rise in plasma catecholamines sufentanyl and alfentanyl are possibly more effective during CABG procedures although the fentanyl series appear more effective in abolishing the endocrine response to surgery, the clinical importance of this difference is still unproven with the administration morphine, there is no improvement in postoperative nitrogen balance

21

 

Opioid Agonists and Antagonists Tolerance and Opioid Abuse addicted patients have a number of problems important to anaesthesia these include, 1.

bact acteri erial end endocar carditis

- es esp peci eciall ally tr triicu cusp spiid

2.

septi septicc pulm pulmon onar ary y and and syst system emic ic em embo boli liza zati tion on

3. 4.

systemic sepsis thrombophlebitis

5.

mycotic an aneurysm

6.

card cardia iacc tam tampon ponad adee and and dy dysr srh hythm thmias ias

7.

pulmonary oedema

8.

pul pulmonar onary y asp aspiira rati tion on and and abs absce cess sses es

9.

pulmonary hy hyper erttensi sio on

10 10..

tal talc gran ranulomata ata

11. 11.

neph ephroti roticc ren renal al dise diseas asee

r est strr i cti cti ve lung di se sea ase and an increased PA-aO2 gradient are particularly common

chronic morphine administration causes adrenal hypertrophy and impaired cortisol secretion other problems which occur with increased frequency in addicted patients include, 1.

viral iral an and d non-v on-viira rall hepat epatiitis tis

2.

HIV infection

3.

osteomyelitis

4.

muscle muscle weakness weakness associated associated with with rhabdom rhabdomyo yoly lysis sis and myoglob yoglobin inuri uriaa

5.

neuro eurollog ogiical cal com compli plicati cation onss

- ttrran ansv sver erse se myel eliitis - encephalitis - cerebral abscesses

routine management of these patients should not involve the avoidance of opioids, and these should be used on an as required basis, as for any patient  patients with an acute overdose are frequently frequently hypotensiv hypotensive, e, bradycardic, hypotherm hypothermic, ic, apnoeic or  hypoventilating, and have a full stomach due to decreased motility

22

 

Opioid Agonists and Antagonists Allergic and Adverse Effects true allergic reactions to the opioids are rare most patient claiming to be "allergic" to opioids have simply suffered adverse effects, eg. pruritis fentanyl and pethidine have both been associated with ana anaphylact phylactoi oid d r eacti actions ons local reactions are thought thought to be due to local release of histamine, histamine, or result from additives ampoules of fentanyl do not contain preservatives, however vials do

 pe  pethid hidine ine is unique, in that co-administration with monoam noami ne o oxi xi dase ase inhi i nhib bi to torr s may result in the ma maliligg nant ne neur urole olept pt syndrom syndrome e, resulting in, a.

hyperthermia

 b.

labile labile arterial BP BP

c.

respiratory de depression

d.

convulsions an and co coma

thus, in patients on MOA inhibitors, fentanyl or morphine are safer choices fentanyl, alfentanyl and sufentanyl are not te ter atogeni atogenic  c   older studies implicated the older opioids, however, the results were compromised by concomitant concom itant respiratory depression depres sion the fentanyl series cause ca use no alteration of uterine blood flow, uterine tone or maternal/foetal acid-base balance

23

 

Opioid Agonists and Antagonists MORPHINE Central Nervous System the primary actions of morphine on the CNS are, i.

analgesia

ii.

redu reduce ced d lev levels els of of con consc sciiousn ousnes esss

iii.

changes in in mo mood

iv.

mental cl clowding

a significant feature of the analgesia is that it occurs without loss of consciousness some patients may also experience euphoria given to pain-free subjects, morphine may lead to dysphoria, with increased fear and anxiety e xcitatory effects effects nausea nause a & vom vomi tin tingg may also occur and these are due to excitatory the balance between excitation and depression depends markedly on the species in man, depressive effects predominate and analgesia is said to be due to, i.

altered perception

ii.

eu eup phoria an and se sed dati ation

iii.

elev elevati ation on of th thee pai pain n th thres resho hold ld

clinically, morphine is more effective in relieving constant, dull pain than sharp, intermittent pain the relief of pain by morphine is relatively selective, in that other sensory modalities are  preserved, ie. touch, vibration, vibration, v vision, ision, hearing hearing etc. this selectivity of morphine is greater than many other drugs that act on the CNS, a.

N2O at 20 to 40%, analgesia is ≡t 15mg morphine, but produces a marked impairment of  consciousness, mental functioning, immediate & delayed memory

 b.

ether & alcohol marked sedation impaired motor coordination, intellectual acuity, emotional stability, and judgment

for a given degree of analgesia, the mental clouding produced by morphine is much less than other agents and qualitatively different morphine rarely produces the garrulous, silly & emotionally labile behaviour seen with alcohol or  the barbiturates opioids obtund the response to pain at several loci within the CNS not only is the sensation of pain diminished, but the affective response is also altered intrathecal administration of morphine can result in profound segmental analgesia, without significant alteration of motor or sensory function termed by Cousins as " sele  seleccti ve spi spi na nall ana nalge lgesia sia" morphine morph ine raises the ICP, due to PaCO2 induced vasodilation, subsequent to depression of the CNS response to hypercapnia

24

 

Opioid Agonists and Antagonists Pharmacokinetics  Abso  Abs orpt rption ion & D i st stri ri bution ution the absorption of morphine morphine after oral aadmin dministration istration has long been stated to be poor and unpredictable this, together with the high h hepatic epatic extraction ratio ~ 0.7 , has steered stee red usage away from the the oral route more recent studies have shown the oral bioavailability  to  to be only moderate moderate but reasonable reas onable reproducible ~ 15-49%  (G&G) following IV administration, morphine rapidly leaves the blood stream the distribution half life, tα½ ~ 1.65 min, the drug rapidly entering the parenchymal tissues of the liver, lung, spleen, kidney, adrenal & thyroid however, only small amounts enter the brain a relatively lesser amount enters skeletal muscle, however due to its large mass this accounts for  the major fraction of morphine in the body serum concentrations are low, reflecting the high VdSS ~ 3.2 l/kg   plasmaa prot  plasm  prote ein b bind indii ng ~ 33% only small amounts cross the BBB, however significant amounts cross the placenta and result in neonatal respiratory depression the elimi e limination nation half-life, tβ½ ~ 180 min

B i otr ansfo nsforr mati on & E xcr xcre eti on less than 10% is excreted unchanged in the urine in the first 24 hrs the major pathway for elimination is conjugation in the liver with glucuronic acid

→

the urine and bile as morphine-3-glucuronide

 N-demethylation does occur but this is a minor  N-demethylation minor pathway pathway the average adult plasma half-life ~ 2.5-3 hrs, may be slightly shorter in young patients and longer  in the elderly over 90% of the administered administered dose is excreted in the first 24 hrs however traces of both free & conjugated morphine are found in the urine ≤ 48 hrs only a small fraction, ~ 7%, is excreted in the feces

25

 

Opioid Agonists and Antagonists Variations in Response, Adverse Reactions & Precautions morphine and its related opioids produce a number of unwanted sid  side e-eff -effe ects, a.

nausea & vomiting

 b.

mental mental clouding clouding,, drowsiness, dysphoria dysphoria

c.

raise aised d biliar ary y tra ract ct pre ress ssu ure

NB: these occur commonly , though, many patients do not experience such effects allergic phenomena phenomena to the opioids do occur, though, these are a re rare and usually only mild anaphylaxis has been reported, ? sudden death in addicts a number of factors alter individual sensitivity to the opioids, including the integrity of the BBB, morphine administered to the mother prior to delivery may cause severe respiratory depression in the newborn other opioids are not as dependent upon the BBB for entry to the CNS and are relatively less selective for the neonate, e.g. pethidine conditions in which morphine should be used with caution, a.

redu reduce ced d circ circu ula lati tin ng bloo blood d volu olume

 b.

decreased respiratory reserve - obesity - kyphoscoliosis - emphysema - obstructive airways disease (*cor pulmonale) - asthma

c.

hypothyroidism

d.

multiple sclerosis

e.

head inju injuri ries es wit with h tth he possi possibi bili lity ty of ra rais ised ed ICP ICP

f.

prostatic hypertrophy

I nt nte er act ctii ons Wi Witth Oth Othe er D r ugs the depressant effects of some of the opioids may be exaggerated, or prolonged by, a. phenothiazines  b.

tricyclic tricyclic antidepressants antidepressants

c.

MAO inhibitors

the mechanisms mechanisms for these interactions are poorly understood, however for some of these drugs there appears to be receptor/transmitter interactions obviously, any other direct CNS depressant is contraindicated in the presence of morphine

26

 

Opioid Agonists and Antagonists CODEINE classified as a simple, or mild analgesic, codeine is often used in low doses as an oral analgesic  produces antitussive antitussive and constipating constipating effects effects at doses below those required required for signifi significant cant analgesia given s.c., 120 mg of codeine is equi-analgesic to 10 mg of morphine, however there is no advantage of the form former  er  unlike morphine, has a higher oral / parenteral potency ratio ~ 2/3 ~ 10% of the administered dose is demethylated to morphine orally, 30 mg of codeine is equi-analgesic to 600 mg of aspirin, however, the effects of the two are additive, and occasionally synergistic

HYDROMORPHONE 2 mg hydromorphone ~ 10 mg morphine  but the drug is more effective effective than morphin morphinee when given given orally  available in tablets, rectal suppositories, & solutions

OXYCODONE actions and potency similar to morphine, however, like codeine it is ~ ½ as effective orally as  parenterally  parenterall y available as 5 mg tablets, solution and in combination with other analgesics average dose ~ 5-10 mg q6h

APOMORPHINE is a dopaminergic agonist , used for its action on the CTZ to induce emesis it has minimal analgesic properties obtained by the exposure of morphine to strong mineral acids

27

 

Opioid Agonists and Antagonists PETHIDINE is a phe  pheny nylp lpii peri dine derivative, introduced by Eisleb & Schaumann in 1939, originally studied as one of a number of atropine-like agents there are a number number of closely related cogners, i.

alphaprodine

ii.

diph diphen enox oxy ylate late (+ atro atropi pin ne = LOMOT OMOTIL IL))

iii.

fentanyl

iv.

alfentanyl

v.

sufentanyl

vi.

lofentanyl

there are two main uses of pethidine, 1.

prem premed ediica cati tion on pr prio iorr to to anae anaest sth hes esia ia

2.

anal analg ges esiia in in ac acu ute, te, o orr ch chro ron nic pai pain n

Central Nervous System  produces a pattern of effects similar, similar, but not identical, identical, to morphine morphine  pethidine,  pethidin e, and/or its metabolites, metabolites, may be more potent potent at κ-receptors onset of analgesia (s.c./i.m.) is ~ 10 min, however the duration, 2-4 hrs is slightly shorter than morphine, therefore more frequent administration is required quantitatively, 80-100 mg pethidine ~ 10 mg of morphine at these doses, the analgesic, sedative and euphoric effects of the two agents aare re almost identical  produces  produ ces corneal analgesia analgesia and hence hence abolishes abolishes co corr ne nea al r eflexe lexess stimulates the CTZ and the labyrinthine apparatus   →  N,V & dizziness dizziness EEG changes are similar to morphine, however they may persist for several days due to the  presence of norpethidine  prolonged  prolong ed administration administration of large large quantities quantities may result in in accumulation accumulation of norpethedine norpethedine & CNS convulsions usually usuall y doses > 1000 mg/day mg/day for several days (adult), but has been reported aatt lower doses

Respiratory System at equipotent analgesic analgesic doses respiratory depression is similar, similar, however, respiratory rate is less effected less & tidal volume more  peak depression occurs ~ 1 hr after i.m. injection injection and tends to return to n normal ormal by 2 hours these effects are antagonised by naloxone

28

 

Opioid Agonists and Antagonists Cardiovascular System in usual doses, has no significant untoward effect on the CVS there is a small increase in peripheral blood flow due to a decrease in arteriolar and venous tone, though, unlike morphine there is no histamine release myocardial my ocardial contractility is not depressed and a nd the ECG unaltered due to increased PaCO2 due to respiratory re spiratory depression, cerebral vasodilation vasodilation and raised ICP are similar to morphine

Smooth Muscle like morphine, pethidine has a spasmogenic effect on certain smooth muscles, however the intensity is much less relative to its analgesic action thus, pethidine is the agent of choice for renal or biliary colic gastric emptying is markedly reduced, altering the kinetics of orally administered drugs, e.g.  paracetamol in pregnant pregnant mothers mothers these effects are not reversed  by  by metoclopramide therefore, the administration of opioids in obstetric practice, where emergency anaesthesia may  be required, required, increases the risk of Mendelsonn's Mendelsonn's syndrom syndromee the uterus is mildly stimulated by pethidine, however the effects are clinically insignificant  pethidine  pethidin e does not cause as much constipation constipation as morphine morphine and this this may relate relate to its shorter  duration of action

Pharmacokinetics  pethidine may  pethidine may be admini administered stered orally, orally, s.c., or i.m. variable oral bioavailability ~ 45-75%, reaching peak plasma concentrations at ~ 2 hrs  plasma concentration concentrationss after i.m. injection injectionss show marked variation variation,, especially in in surgical surgical patients, patients, though, maximum maximum levels are normally achieved by ~ 20 mins following i.v. injection, elimination is multiphasic, with rapid and extensive extravascular  distribution which is essentially complete in 30-45 minutes, and a terminal half-life, t ½β ~ 3 hrs (some report ~ 8 hrs)  plasmaa  plasm ~ 60  p ein b bind indi i ngh ~ 700-1300 % 300 ml/m  plasma prot clrote clearance earance is high hig 700-1 ml/min in and and less than 5% of of the admini administered stered dose is excreted unchanged unchanged  pethidine  pethid ine is is metabolised metabolised in the liver, liver, a.

N-demethylation ~ 1/3

 b.

 pethidine ine hydrolysis  pethid norpethidine

c.

     

→

norpethidine

→ →

 pethidinic  pethidin ic acid norpethidinic acid

conjugation  of both acid products

norpethidine ~ 50% analgesic activity, however its convulsant activity is ~ 2x that of pethidine

29

 

Opioid Agonists and Antagonists urinary excretion of pethidine is pH dependent, up to 25% of the drug may be excreted unchanged in the urine if it is highly acidified , however this does not significantly affect plasma levels r ena nall fail failure ure may cause accumulation of the active metabolites of pethidine in patients with cirrhosis the bioavailability is increased, the plasma clearance decreased and the half lives of both pethidine and norpethidine are prolonged   patients have higher serum concentrations for a given dose compared to young adults elderly  patients  possibly due to decreased protein protein binding binding,, plasma clearance clearance and VdSS , therefore they should receive lower doses

Pregnancy & Neonatal Considerations commonly used for pain relief during labour   pethidine  pethidi ne crosses the placenta readily readily and can resu result lt in neonatal neonatal respiratory respiratory depression umbilical cord:maternal blood ratios vary between 0.8-1.0:1.0 metabolites may be responsible for some of the neonatal depression, however, cord norpethidine concentrations are generally low the neonatal clearance of pethidine is markedly lower than the adult and highly dependent upon urine flow

neonates may take up to 6 days to completely eliminate the drug, tβ ½ ~ 24 hrs

Dosage & Adverse Effects recommended adult dose is 75-100 mg i.m., repeated 3 hrly as required adverse effects (essentially = morphine), a.

respiratory de depression

 b.

nausea & vomiting vomiting

c.

drow drowsi sine ness, ss, dy dysp spho hori ria, a, impa impair ired ed cereb cerebra rati tion on

d.

syncope

may produce produce a severe drug interaction with the MA O inhibit NB:  potentiation ors, possibly due to of pethidine pethidine biotransformation biotransformation in the liver, liver,inhibito

→

excitation, convulsions, hyperpyrexia, hypotension, and respiratory depression

 pethidine causes constipation  pethidine constipation far less than morphi morphine ne large doses produce muscle tremors, dilated pupils, hyperactive reflexes and convulsions

30

 

Opioid Agonists and Antagonists FENTANYL a synthetic opioid, related to the phenylpiperidines, with a  p  po otenc ncyy ~ 80 80xx morph rphine ine  like morphine fentanyl is primarily µ-receptor agonists in equianalgesic equianalgesic doses they produces about the same degree of respiratory depression, however, this is of shorter duration than pethidine or morphine ?? the sedative and hypnotic activity is less than the other two agents (G&G doesn't agree with this last statement s tatement from W&W) there have been reports of postoperative respiratory depression after fentanyl, despite its short duration of action fentanyll is noted for its rapid onset and short duration of action fentany the euphoric and hypnotic effects are antagonised by naloxone, however are relatively unaffected  by droperidol, with which it is commonly used to provide neurolept analgesia  provided  provi ded respiration respiration is maintai maintained, ned, even with with very very large large doses cardiovascular cardiovascular stability is  preserved at high doses, fentanyl may increase the rigidity  of   of respiratory muscles, decreasing compliance the main uses of fentanyl are, a.

balanced anaesthesia

+ O2 / N2O / volatile

 b. c.

neurolept neurolept analgesia "cardiac" anaesthesia

+ droperidol + O 2 ± volatile or other supplem s upplement ent

droperidol acts as an α-blocker and vasodilation is common with the later practice however, CVS stability is good and any hypotension is easily treated with appropriate fluid replacement occasionally used in high-dose anaesthesia due to CVS stability and the reduced catabolic response to trauma, however, respiratory depression is common and reversal with naloxone may lead to agitation and a withdrawal-like syndrome the usual adult dose is 100-200 µg and up to 600 µg may be given if respiration is controlled

Pharmacokinetics usually described by a 3 compartmental model > 98% of the administered dose is removed from the plasma within the first hour   brain levels levels parallel those in blood, blood, with distribu distribution tion constants, constants, i.

t ½α1

~ 1-2 minutes

ii.

t ½α2

~ 10-30 minutes

iii.

t ½β

~ 2-4 hours

spectral edge studies suggest administration administration is best ~ 5 minutes prior to known noxious stimuli alternatively, alternativel y, a large bolus may be administered administered to saturate both brain receptors and non-receptor  storage sites

31

 

Opioid Agonists and Antagonists animal studies show > 50% of the administered dose may be held in muscle & ~ 20% in fat the high lipid solubility and high V dSS limi  limitt hepatic access a ccess to the drug and contribute to the wide variation in plasma levels during the distribution phase the high clearance and hepatic ER minimise enterohepatic circulation of fentanyl however, decreases in hepatic blood flow decrease elimination of fentanyl  primarily  prim arily metabolised metabolised by N-dealkylation N-dealkylation,, the activity activity of metabolites metabolites being being unknown unknown the high pKa ~ 8.4, results in > 90% being in the ionised form  plasma prot  plasma  prote ein b bind indii ng ~ 40% the terminal half life may be prolonged with either very large, or repeated administration and this may be responsible for the occasional case of postoperative respiratory depression

Relative Potencies Agent

Relative Potency

Anaestheticc Dose Anaestheti

Morphine

1

~ 1- 3

Alfentanyl

20

~ 50-200 µg µ g/kg

Fentanyl

80

~ 50-100 µg µg/kg

Sufentanyl

800

~ 2-20

Lofentanyl

6,000

32

research

mg/kg

µg/kg

 

Opioid Agonists and Antagonists

Pharmacokinetic Data Morphine

Pethidine

Fentanyl

Alfentanyl

Sufentanyl

8

8 .5

8.4

6.5

8

% Unionized

23%

< 10%

< 10%

90%

20%

τOctanol:H2O

1.4

39

813

145

1778

t½α1 (min)

1.0-2.5

1-2

1-3

1-2

t½α2 (min)

10-20

5-15

10-30

4-17

15-20

t½β

2-4

3-5

2-4

1-2

2-3

3-5

3-5

3-5

0.4-1.0

2.5-3.0

15-30

8-18

10-20

4-9

10-15

0.8-1.0

0.7-0.9

0.8-1.0

0.3-0.5

0.7-0.9

Agent  pKa'

(hrs)

VdSS Cl

(l/kg)

(ml/kg/m)

ER 

33

 

Opioid Agonists and Antagonists OPIOIDS WITH MIXED ACTIONS agents in this group bind bind to the µ-receptors, µ-re ceptors, therefore can compete with other agents, however, they either exert no effect, co comp mpe eti titi tive ve anta antagg oni onists sts, or only a limited effect, p  pa artia rtiall agonist gonistss drugs such as nalorphine, cyclazocine and nalbuphine are competitive antagonists at µ-receptors, thereby antagonize the effects of morphine however, these agents act as p &σ  pa artia rtiall agonist gonistss at other receptors, κ   &  pentazocine qualitativ qualitatively ely resembles resembles these three agents, but is a much much weaker antagonist antagonist at µ-receptors and stronger agonist at κ -receptors -receptors  propriam and and buprenorphine buprenorphine have have partial agonist actions actions at µ-receptors µ-rece ptors

PENTAZOCINE  pentazocine was synthesised as a part of a deliberate  pentazocine deliberate effort to dev develop elop an effective effective analgesic analgesic without the potential for abuse this latter hope is not the case, cas e, though, considerably less so than morphine morphine is a be benzmor nzmorphan phan of similar potency to morphine and in the N-allyl derivative of phenazocine it has both agonist actions and weak antagonist antagonist actions the large allyl substituent, on what would be the N 17 position of morphine, is a common structural feature of a number of the opioids with mixed agonist/antagonist actions (see G&G 7th Ed., p520) the analgesic and respiratory depressant actions of the racemate ra cemate are largely due to the l-isomer  a dose ~ 20-30 mg is equipotent to 100 mg of pethidine, or 10 mg of morphine

C entr ntra al N Ne er vous vous S Syst yste em the pattern of CNS effects produced by this drug are generally similar to those of morphine, including analgesia, sedation and respiratory depression however, pentazocine resembles cyclazocine & nalorphine in that it produces a type of analgesia which differs from that of morphine, the euphoria and sense of well being are absent 

→

 pentazocine clearly clearly interrupts interrupts nociceptive nociceptive input input in the sp  spina inall cord , while morphine also acts at supraspinal sites in producing analgesia

thus, it is probable that the analgesic effects of pentazocine are mediated by actions primarily at

κ-receptors

increasing the dose > 60-90 mg results in nalorphine-like dysphoric  and  and psychotomimetic effects, these can be antagonised by naloxone but not nalorphine and are probably due to actions at

σ-receptors

 pentazocine acts as a weak antagon a ntagonist ist at µ-receptors, being only ~ 1/50th as potent as nalorphine it does not  antagonise   antagonise the respiratory depression produced by morphine, however when given to addicts may precipitate withdrawal symptoms

34

 

Opioid Agonists and Antagonists Respiratory System  pentazocine produces produces a similar degree degree of respiratory depression to m morphin orphinee at equi-analgesic equi-analgesic doses, however, increasing the dosage above a bove 30 mg does not produce a proportionate proportionate increase in respiratory depression studies indicate that a ce ceii ling li ng eff ffe ect  is reached at ~ 60 mg in a 70 kg man the respiratory effects can be reversed by naloxone

C ar di ovascular vascular S Syst yste em differs from morphine as does not  produce  produce hypotension hypotension or bradycardia actually produces a slight rise in HR & BP, suggesting that it may increase the MRO2 in patients with MI, pentazocine has been shown to elevate the LVED pressure and should therefore be avoi  in subjects with I H D avoide ded  d  in  plasma catecholami catecholamines nes are increased and these these may account account for these effects effects

G I T  similar for the other opioids →  delayed gastric emptying and reduced propulsive activity in the intestines

Parmacokinetics may be administered by either the oral, i.m. or i.v. routes, though, there is considerable intersubject intersu bject variation it is well absorbed from the GIT and other sites maximum serum concentrations are reached at 15-60 min after i.m. injection and at 1-3 hrs after  oral administration  plasmaa ha  plasm halflf-lilife fe ~ 2-3 2-3 hrs first pass metabolism is extensive and oral bioavailability ~ 20% elimination is largely via biotransformation in the liver 

→

oxidation of the terminal methyl groups & glucuronidation, then excretion in the urine

greater than 60% appears in the urine after the first 24 hrs there is considerable intersubject variability in the rate of biotransformation and this may account for the variation in analgesic response marketed as 50 mg tablets and as 30 mg/ml injectable solution

35

 

Opioid Agonists and Antagonists  Adve  Adv erse E ffe ff ects although pentazocine has a low abuse potential, it can produce both psychological and physical dependence tablets marketed in the USA with naloxone to remove possible source for IV use, naloxone is hydrolysed in the GIT  because it is a weak antagonist at µ-receptors it may produce produce wi withdr thdraw awal al symptom symptomss in addicts as for morphine, the following are side-effects, a.

seda sedati tio on, resp respiira rato torry dep depre ress ssiion

 b.

dizziness, dizziness, sweating and and nausea

c.

raise ICP

d.

may cause cause nalo nalorp rphi hine ne-l -lik ikee dys dysph phori oriaa at at hig high h doses doses

- rarely vomiting vomiting

care should be taken where there is reduced respiratory or liver reserve

BUTORPHANOL  butorphanol  butorph anol is a morphin morphinan an cogner with with a profile profile of actions similar similar to pentazocine pentazocine it is about 3.5-5 times as potent as morphine, morphine, average dose ~ 2-3 mg i.m. oral bioavailability is low, ~ 15-20% the onset, peak and duration of action are similar to morphine the plasma elimination elimination half-life ~ 3 hrs respiratory depression exhibits a ce ceii ling li ng eff ffe ect  and can be reversed by naloxone like pentazocine it increases BP, LVEDP & PAP, therefore, should be avoided in IHD the incidence of psychotomimetic effects is lower, but qualitatively similar, to pentazocine undergoes extensive liver metabolism, mainly hydroxylation to hydroxybutorphanol but also to norbutorphanol (10%), followed by urinary excretion (70%) readily crosses the placenta and foetal levels may exceed maternal levels same precautions and recommendation c.f. pentazocine

36

 

Opioid Agonists and Antagonists  NALBU  NA LBUPH PHIN INE E is structurally related to both oxymorphone and naloxone, and has a spectrum of activity similar  to pentazocine and nalorphine however, nalbuphine nalbuphine is more potent an antagon a ntagonist ist at µ-receptors than either e ither of these agents hence is less likely to produce the dysphoric, or psychotomimetic effects it is approximately equipotent to morphine, the usual dose 10 mg i.m. the onset of effect after parenteral administration is 2-3 min/i.m, or 15 min/i.v. the duration of action is ~ 3-6 hrs its predominant site of action, like pentazocine, is the κ -receptors -receptors of the spinal cord respiratory depression is similar to morphine, however, like other agents in this group exhibits a  and is reversed by naloxone ceiling effect  and  elevate BP, HR, LVED NB: unlike the other members in this group, nalbuphine does not  elevate  pressure, PA pressure, or increased cardiac work in IHD IHD patients nalbuphine is metabolised in the liver and the tβ½ ~ 5 hrs oral bioavailability is ~ 20-25%

BUPRENORPHINE is a semisynthetic, highly lipophilic derivative of the opium alkaloid thebain approximately 25-50 times as potent as morphine, usual dose ~ 0.3-0.6 mg like the preceding agents, buprenorphin buprenorphinee is a partial agonist at µ-receptors, µ-rece ptors, however it has a very high affi affi nity  for these and the respiratory depression, while showing a ce ceii liling ng effe ff ect , is poorly reversed by naloxone  produces analgesia analgesia and other effects effects similar to m morphin orphine, e, including including CVS it is well absorbed from most routes, including the sublingual  peak blood concentration appear at 5 min/i.m., min/i.m., and at 2 hrs/s.l., or oral  plasma protein protein bindin binding g is ~ 96%  plasma half-lif half-lifee is ~ 3 hrs, however, the duration duration of action is longer, longer, sometimes sometimes up to 6 hrs,  probably due to tissue bindin binding g  both N-dealkylation N-dealkylation and conjugation conjugation occur in in the liver, liver, however most of the the drug is excreted unchanged in the faeces may produce a delayed onset withdrawal syndrome several days after cessation of the drug

37

 

Opioid Agonists and Antagonists OPIOID ANTAGONISTS under ordinary circumstances the drugs in this group produce few effects unless drugs with opioid agonist activity are given prior  however, when the endogenous opioid system is activated, as in shock, the administration of an antagonist along has demonstrable effects the common drugs in this group include levallorphan, nalorphine and naloxone the common common structural difference with these agents is substitution at the N17 moiety for a larger  group,

 N17: -CH3 →  

allyl (-CH2-CH=CH2) →

nalorphine

→

levallorphan

a.

morphine

 b.

levorphanol levorphanol

c.

oxymorphone   →

 

naloxone

occasionally cogners cogners are produced which are competitive competitive antagonists at µ-receptors, µ-rec eptors, but have  partial agonist actions at other receptors nalorphine was the first such agent produced in the search for a nonaddictive opioid analgesic, however, the marked dysphoria produced limited its clinical usefulness as an analgesic nalorphine did, however, remain the treatment of choice for opioid overdosage for many years levallorphan has similar actions but is far more potent than nalorphine other cogners, such as naloxone, naloxone, have apparently no agonist agonist action ac tion and appear to bind to all a ll classes of opioid receptors, albeit with different affinities

 NALO  NA LOXO XONE NE as stated, is the N -allyl de derr i va vative tive of the opioid analgesic oxymorphone it possesses almost no agonist activity and if administered de novo has almost no clinical effect it antagonises the effects of the opioid analgesics and the agonist/antagoni agonist/antagonist st group such as  pentazocine and butorphanol butorphanol but but not buprenorp  buprenorphine hine (NB: MCQ) the duration of action after i.v. administration administration is short ~ 20 mi mi n naloxone rapidly metabolised (in thevai liver, glucuronidation very high is first pass metabolism i.v. administration bioava bioa i lab labiiprimarily lility ty ~ 2%)bynecessitating naloxone is the drug of choice for the treatment of opioid respiratory and CVS de naloxone depression pression the usual adult dose is 0.1-0.4 mg i.v. also als o avail availabl ablee for for neon neonatal atal us use, e, usu usual al dose dose 0.01 0.01 mg/kg g/kg (now (now use use adult adult streng strength th)) due to the short s hort duration of action monitori monitoring ng is essential and repeated repea ted doses may be required

38