6. Analgesics Flashcards
Problems with OSA + Death in paeds w/ codeine
Ultra-rapid metabolisers” are more likely to have higher than normal amounts of morphine in their blood after taking codeine.
what sub are derived prepro-opiomelanocortin
Melanocyte stimulating hormone β-endorphin Adrenocorticotrophic hormone (ACTH) β-lipotropin, and Met-enkephalin
Endog opiod - all peptide - unrelated to lipids (arachadonic acid eg)
The action of opioids on the cell is mediated by:
Inhib what channel & where
Inhibits what
Inhib what else
Net effect
Inhibitory G proteins (Gi).
Opioids have been proposed to inhibit the neurotransmitter release presynaptically by inhibiting voltage-dependent calcium channels.
Reduced calcium influx into synaptic terminal results from the inhibition of adenylate cyclase (AC), the enzyme which converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP).
Opioids also act Indirectly by increasing the outward K + current, shortening repolarisation phase and therefore the duration of the action potential.The net effect is to reduce cell excitability.
Canabinoids
Avail PO & Smoke
whats active component
what blocks its action
the production of what is reduced
what do they do to IOP
9-tetrahydrocannabinol 9THC - active component
10-20%
10-30
Naloxone and other opioid receptor antagonists block the analgesic actions of cannabinoids.
Synthetic cannabinoids reduce arachidonic acid-induced inflammation by inhibiting eicosanoid production.
Cannabinoids lower intraocular pressure (not increase).
Naloprihne
Pentazocine
Nalorphine is an opioid agonist-antagonist that is equally potent with morphine as an analgesic but is not clinically useful due to a high incidence of dysphoria.
It can displace opioid agonists from mu receptors, helping to reverse respiratory depression.
It is not effective at reversing respiratory depression due to barbiturates / benzodiazepines.
Pentazocine is also an opiod agonist-antagonist.
Arachidonix acid whats it derived from formed by action of what
What do they following do to plt and vessel calibre
TXA2 -
PGI2
PGE2 - whats it role
Arachidonic acid is derived from membrane phospholipids formed by the action of phospholipase A.
TXA2 induces platelet aggregation and adhesion and also causes vasoconstriction.
PGI2 causes vasodilatation and decreases platelet adhesiveness.
PGE2 participates in the initiation and maintenance of parturition and has a role in thermoregulation.
NSAID intolerant asthmatics
NSAID-induced reactions appear to be caused by the inhibition of cyclooxygenase-1 (Cox-1); this in turn activates the lipoxygenase pathway, which eventually increases the release of cysteinyl leukotrienes (Cys-LTs) that induces bronchospasm and nasal obstruction.
With regard to the metabolism of arachidonic acid (AA) in NSAID-intolerant asthmatic patients, the following changes have been observed:
A low production of prostaglandin E2, seemingly due to deficient Cox-2 regulation
An increased expression of leukotriene-C4 synthase and
A reduced production of metabolites (lipoxins) released through the transcellular metabolism of AA.
Dorsal horn
what & wheere
modulators
The dorsal horn is the site where primary afferents terminate, and there is a complex interaction between these afferent fibres, local intrinsic spinal neurones and descending fibres from the brain.
A number of substances (peptides, catecholamines and indoleamines) have been implicated as neurotransmitters at the dorsal horn, and when released they modulate peripheral nociceptive input.
They include:
Substance P Serotonin Noradrenaline Acetylcholine Glutamate Adenosine. Reflex activity also modulates peripheral nociception.
Alfentanil is what
Soubility vs fentanyl
Vd
Protein bind
S.E
Why is the onset of Anfentanil qquicker
Alfentanil is a phenylpiperidine opioid analgesic that has a rapid onset and short duration of action.
Alfentanil is less lipid soluble than fentanyl making it less potent.
Consequently it has a small volume of distribution coupled with high plasma protein binding (92%).
The main side effect is respiratory depression and it also causes sedation.
Unionised molecules cross membranes (that is, blood-brain-barrier) more readily than ionised molecules.
Alfentanil and fentanyl are weak bases and as such the ratio of ionised to unionised molecules depends upon the pKa of the parent compound in relation to physiological pH according to the Henderson-Hasselbalch equation.
pKa of alfentanil is 6.5
pKa of fentanyl is 8.4
At a pH of 7.4 89% alfentanil is unionised compared with 9% fentanyl.
Therefore the onset of alfentanil is quicker than fentanyl.
The offset of action and terminal half life (T1/2) is dependent on the relationship between clearance and volume of distribution
Entonox
mix of
effective vs pehtidine
onset max effct
low dose added
side effects for baby?
Entonox is a gaseous mixture of nitrous oxide and oxygen and has been has been used since the 1960s.
It is twice as effective as pethidine at providing labour analgesia, but inhalation should begin as soon as the uterine contraction is felt, because it takes forty five seconds before the maximum analgesic effect is achieved.
Low dose isoflurane and sevoflurane have been given in addition to Entonox which has demonstrated an increased analgesic efficacy over Entonox alone.
Combining the analgesic effects of Entonox with other analgesics agents provides superior analgesia to using Entonox alone.
Entonox crosses the placenta but it is not known to cause significant side effects in the baby
NSAIDs renal complications
Reversible renal insufficiency (haemodynamic acute renal failure or kidney injury) is the most common complication of NSAID.
PG syntehsis reduciton - HD insuff
Fentayl Dose + response graph
dose and response plotted graphically is a rectangular hyperbola
Tramadol
µ-opioid receptor agonist
Inhibition of reuptake of norepinephrine and serotonin.
Low affinity binding of the parent compound to µ-opioid receptors
higher affinity binding of the M1 metabolite
Metabolic pathways are N- and O-demethylation (phase I reactions) and conjugation of O-demethylated compounds (phase II reactions).
Most potent analgesic - Mono-O-desmethyl-tramadol
Papaveretum
Morphine
Codeine
Papaverine
Thebaine.
less potent than morphine (20 mg of papaveretum being equivalent to 12.5 mg of morphine), and has more sedative effects.
Noscapine (narcotine) is associated with foetal polyploidy and was removed from the preparation.
elaxant effect on vascular smooth muscle and is used in the management of an intra-arterial injection of thiopentone.
Remifentanil
is what
acts where
peak effect
metabo by
context sense
release his?
Remifentanil is a synthetic anilidopiperidine derivative, which is a pure μ agonist.
The peak effect is between one and three minutes.
It is metabolised by non-specific tissue esterases, which are not affected by genetics, renal failure, hepatic failure or age.
It has a context-sensitive half time of three to five minutes and does not accumulate in the tissues.
It is not associated with histamine release.
Agonists or no at op receptors
Buprenoprhine
Pentazocine
Diamorphine
Naloxone & naltexone
Buprenorphine (is an agonist at MOP receptors but antagonist at KOP receptors)
Pentazocine (has weak antagonist at MOP receptors but agonist at KOP receptors the latter responsible for its analgesic action) are the only drugs listed which are opioid receptor agonists. Buprenorphine is a partial agonist while pentazocine is a mixed agonist-antagonist.
Diamorphine (diacetyl morphine) is an inactive prodrug, which acts via its active derivatives, morphine and 6-0-acetylmorphine.
pka 7.6
rapid metab liver to active metab
high 1st metab
x2 ptoency
more rapid actionn <= greater lip solubil
more euphoric
better antitussive
Naloxone and naltrexone are opioid antagonists, and the former has a much shorter duration of action.
Alfentanil
Potency v Fentanyl
why
lipid sol
prot bind
Onset / Offset vs fentanyl - why
Alfentanil is less potent than fentanyl because of its lower lipid solubility and greater protein binding.
Compared to fentanyl its onset and offset are faster by virtue of the fact that it has a lower pKa (that is, is less ionised at physiological pH) and has a smaller volume of distribution (due to more protein binding).
Fentanyl v Alfentanil
Which is more lipid soluble
When is the onset slower for one of them
Alfent metabolism
High doses of opiod cause
Fentanyl is more lipid soluble than alfentanil, but it has a slower onset of action because it is only 9% unionised in plasma, whereas alfentanil is 89% unionised.
The ionised form of a drug is insoluble in lipid regardless of the lipid solubility of the unionised form.
Alfentanil is extensively metabolised in the liver and its clearance is affected by liver disease, but its clearance is almost completely independent of renal function.
Fentanyl is more potent than alfentanil, which is reflected in the typical intravenous doses of the drugs (100 mcg of fentanyl and 1 mg of alfentanil).
The termination of the action of fentanyl is due to redistribution.
When high doses of fentanyl are given the body’s lipid compartment will become saturated and the termination of action will then be due to metabolism. This is referred to a context specific half life, as the half-time depends on the context in which the drug is used (that is, dose or duration of infusion).
High doses of opioid drugs usually lead to a centrally induced bradycardia (not tachycardia).
Morphine -
Metabolism
End products - %’s
Do they have analgesic property
What other effects do they havehttps://www.brainscape.com/subjects
pka
prot bind
Morphine undergoes hepatic and extrahepatic metabolism
Dealkylation
Oxidation
Conjugation with glucuronic acid
produce approximately 75 - 85% morphine-3-glucuronide (M3G), which is essentially inactive
and 5 - 10% morphine-6-glucuronide (M6G), which has analgesic properties (not antanalgesic).
x10 potency
Although M3G has no analgesic properties it does at high doses cause CNS stimulation (hyperalgesia and myoclonus) not mediated through opioid receptors.
M3G may be an antagonist but this is thought to be functional because M3G does not bind to opioid receptors.
pka 8
prt 30-35%
Diamorphine
Diamorphine (diacetylmorphine) is a prodrug and is metabolised to morphine.
ester hydroylsis -> 6 monacteylmorhpine
then lver metab to morphine
pka 7.6
PO abso - good lip solub
40% prot bound vs 70% remifent
Pethidine
What is the pethidine metabolite
what does it do
Metab - ester hydolysis - pethidinc acid
N demethylation ->
Norpethidine is a metabolite of pethidine, which is excitatory to the central nervous system.
Norpeth
What activity do the alfentanil metabolites have
The metabolites of alfentanil are pharmacologically inactive.
Opiate vs Oiod
Opiate - natural occur sub - morphine like prop
Opiod - general - synthetic sub affin for opiod
Classification / action / ditsrub receptor
GPCR CNS, high conc - nuclei tract soilt periadeq grey cortex thalamus
S.cord,
gitm periheral afferent NT
Classifcication
3 receptor true op
Mu, Kappa, Delta
Morphinbe - bind mU
Subtypes rece
2 mu, 3 kappa 2 detla
Reclassified
Op1 Delta
2 Kappa
3 Mu
New - ORL1 - nociception
MOP DOP KOP N NOP
Is the sigma receptor opiod recptor
No not all classic criteria
Naloxone doesnt reveres
Mu cuases
Analgesia
Miosis
euprhoira
Mu1
Resp depression braady inhib ghut
Preed u2
supra spinal - act brain level
Phys - dependence
Agonst morphine
Delta
analgesia & resp dpression
Spinal level
Enkpehalin
Kappa
Sedatio Misois Resp depress Ibnhib ADH - spinal level Ketocylazaine dependewce dif to u
Opiod level work
presesny gpcr
Closs volt Ca
Stim K efflux
= hyperpol membrane
Reduce CAMP
Overal reduced cell excitableity
Reduction in nocioceptive transmission
Routes admin
IV IM PO TDerm , intratehcall,
PD effects
CNS Analgesia Swedationb Euphoria dsypohira gakllucanation tolerance depend
Dull continm oorlyh lcoal pain viscera
Less effect vs superical & sharp
Neuropathic can be resista
My reduce inteisit
Tolerance - decrease ffect depsite main given con
?? - downreg, decrease endog
Depend
Wdral - after repeat use prolong period - physcical & psycholog sign
Resltessm irtabilm, sweat, cramp V+D
CVs
Mild brady - decrease symp drive & dir affect SA node
Periph Vdil - HIS release, red symp drive - drop bp
Resp effect opiod
Mu recept brainstem
RR fall > TV
Reduce paco2 senstivity
BStem response to hypoxic stim
Antitussive
large dose remi - general muscle rigidityy ++ throcic wall
Other effects of opioid
Direct stim ctz - N+V
Sm muscle tone increase
motility - decrease - delay absoprtion
icnrease biliary pressure - spasm oddi / cosntip
Endocrine
Inhib acth, prolactin, gnrh & increase ADh
U & K - edinger westhpahl ocupmotr - constriction ‘misosis
Some - morhpine - his rela mast cell
Hypot itch bvspam urticatre
Most common after intrachteal
face nose thorse
Central med mech - rev naolox
Onset + duration so different
Morphine, fentanyl,
Terminal half alfent 100min
fent 190
Clear alfent - smaller 6ml/kg min
fent 13ml
Shorter terminal half - smaller Vd
Compare Alfent 0.53 vs
Fentnyl 4 l kg
Fentaynl highly lipid soluble - taken up by fat & muslce
Explains why fentanyl shoprter durationb action vs morphine despite slower clearance (16ml)
High lip solublily vs morphine
crosses BBB faster - more rapid onset
Alfenta poor lip solubil Smaller init Vd Despite - weak base pka 6/5 - unbound near 90% uni Unbi - cross BBB Rapid ecnetral effect
Morphine metab + excreted
Conjugated
M36 - glucorind 700%
M6Gluc 10% - active more ptontet than morphine
Demtthyal normoprhine 25%
Predom excrete urin - conjuagted matob
Remi
Pure Mu gagonist
aniliopiperide opood
methyl ester linkage
Merrtablim unquie
Analgesic GA
Lyophilised powder 1 2 5 remi hcl - glcine buffer
Recon - clear colourless oln
GLyc buffer - not itnratjheca
IV bol 1ug kg infusio 0.025-1ug kg min Peak effect after 1-3min Context sense half - indep infusiont timne cvs stability - w/out effect
Other anaglesic - post remi wear off
S/E
Decrease MAP
Decre HR
Decr contractily & output
Resp dperession
TV & MV
Decr response to hpyxoia / co2
Wooden chest gaba ergec inert mu neuro
relex relax
Not his releiase - no bspam
Cen med vagal act
Min hypotnic / sediative
Decrease GI motil
Low N/V
Metab
Rapid undegeo ester hydrolysis by non sepcifc plasma esterases
to caroxylic derv 300 -1000 les s pteont
Excreted in urine
clerance 40ml k gmin elim t 1 2 10m
Nalbphine
mix agon/ antag
Semisyhtn phenanthrene deriv
Clear colourless soln - inject
10mg ml nublphine
Iv im sc
agonst kapa
Antag U
Analgesia - k , antag resp depress & dewprend U
Se
sedationdizzy vertgio dry mouthj headahce
Inffective cv response to Laryngo
Withdrawl symptoms in addicts
Rev Naloxone
Mode NSAIDs
Draw diagram 213
Ihib COX
Prevent PG & TA2 from menbrae phospholipd
Decrease PGE2 & F 2 - antiilfamm
Red txa2 - reduce plt agreg & addehes
Antipyretic - central PG
Red PG - gastric mucosa = ulceration
Liopox not inhib
ore arachdonic convert to leukotrine - excarb of asthma nsaid
Aspirin irrev - acetlyation - syhtentx new cox for further pg & txa2
Other nsaid reverseble
Fall - cox resume
Diffrence between cox1 & 2 inhibitors
COX - 2 enz COX1 * COX2
Constituve enzyme
Induced site inflam
COX1 - underlie majority ybwated effect - gi irtat, beeldm, nephrtox
PGE PGI 2 -
inhib gastric acid secretion - prortectice effect
RBF reduce as vasodilators
Prlong use - renal fail develop interstil nephrtiits
COX 2 Analgesic, inflamm, pyretic Also prot PG - Hpylori Increase cardiac event? current use those risk GI side effects
NSAID sensitive asthma
20% asthmatics
inhibit COX = more arachidonic acid -> leukotrines
NSAID & bleeding
Platelt fucntion reduced Txa2
PRevent aggreg vasocn
warfarin can be displaced - unpred increased effect
(Se li affect random)
Ibuprofen
Brfuen
Proprionic acid
max 1.8g day
Paed - 20mg/kg
Anti - pyretic, inflamm, anaglesic
Lowest inceidence s/e nsaid
Elim half 2-3hours
Ketorolac &
Acetic acid derivate Pteont anglegisc & antipyeritc Lited anti inflamm Side other nsaid Not ci heprain elim half 5 hours 99% ptoein
Paracetamol
Despite nop effect cox in vitro - classifyt nsaid anglgesia pyrtic
Acetnaildine deritve
moa poor understood
ANti pyreric inhib PG - CNS
Peripoh impulse gen bk sens chemreceport - genet aff nocicpetive
Paracetamol tox
Gluc conjug
exrete urine
N acet p amino benquoquine - tox metb parct
Smal quant normal - rapid metab by glutathione - render harmess
Tox dose - conjugaion stuarted
Glutathione depleete tox accum
Form covalent bond - sulhphydrllgropup hepatocyte - centrilob necorsis - NAC & METho alternation suplly glultathionbe - ppretct vs tox
if 12h ingest
NAC hytsr cystein - glutahtione precure
mehtionine enhance synthesis
Morphine
Does it cause direct myocardial depression
Does it cause hypotension
-what are the causes of this
PAffect ADH
What family is morphine
What family are pethidine & fentanyl
Morphine does not cause direct myocardial depression, although it may cause a bradycardia.
The hypotension associated with its use is because of a decrease in the systemic vascular resistance (SVR) which is due, in part, to histamine release. The histamine release may also cause bronchospasm.
The production of antidiuretic hormone (ADH) is also increased by morphine.
Diamorphine has almost no affinity for the opioid receptor and is a prodrug of morphine.
Phenylpiperidines include pethidine and fentanyl, whereas morphine is a phenanthrene.
Tapentadol
What agonist
also acts
Active metab?
a MOP receptor agonist and blocks the reuptake of noradrenaline.
Unlike tramadol it has not active metabolites.
Opiod receptors
Where are they located
what are they coupled to
How many type
name them
Binding cuases what
Inhib of
increase of
decrease of
activated
Opioid receptors are members of the large family of seven transmembrane domain receptors (rather than just intracellular), coupled to pertussis toxin-sensitive G proteins.
Four types have been characterised and cloned and designated
Delta (DOR) Mu (MOR) Kappa (KOR) and Orphan receptor-like 1 (ORL-1). They each contain between 372 - 400 amino acids and have different molecular weights.
Binding of opioid agonists to the receptors causes:
Inhibition of adenyl cyclase (reducing cAMP levels)
An increase in potassium conductance (the G-protein-activated inwardly rectifying conductance or GIRK)
Inhibition of voltage sensitive calcium channels
A decrease in transmitter release (excitatory and /or inhibitory).
Protein kinase C is also activated.
Opioid receptors are located in plasma membranes of neuronal and non-neuronal cells located at pre-, post- and extra-synaptic sites.
In the CNS they are differentially distributed in the brain and spinal cord.
What are KOR receptors located
Where are DOR recptors
Where are MOR receptors
The expression of kappa receptors (KOR) in the spinal cord is high in laminae I and II, and moderate throughout laminae III - VIII and X.
Delta receptors (DOR) are predominantly in lamina IX (not kappa) with lesser densities throughout laminae III and VIII.
Mu receptors (MOR) are predominantly localised in laminae I and II with moderate expression throughout laminae III - VIII and X.
Enkephalin
Endog pentapeptide
proencephalin
nerve ending GIT
adrenal, medulla
t1/2 brain shorter -
Fentanyl
Can = resp dperssion Neuroax block
also diammorphine
Less so vs morphne - less lip sol - higher delayed resp depresss
Remi - rapidest clearence 40ml kg min
Equiv conversion fent patch -> morhpine
25mcg = 90mg morphine
Equiv dose
morpine = diamorphine = oxycodone
Morphine 10 = po
Oxycodone 5 = po
Diamorphine 3 IM
alfentanil t1.2 clearance vd pka phys ph *vs remi
t1.2 elim 100min clear 6ml kg vd 0.6lkg pka 6.5 phys ph 89& union vs remi 68%
less clearnce v morphine
fentanyl
elim t/12 190
clear 13ml kg
vd 4l
pka 8.4
Pethidine
base
- in more acidic environment = ionised =trapped
prot bind 60% (vs 90% alfent)
phys pH - 5% uní (20% morphine)
lipid soluble x30 vs morphine
reaches peak fetal levels 4h after IM admin
Alfentanil - pKa
solbil vs fenny
metaob where by what
what is also - can affect t1/12
6.5
6x less sol
cyp3a3/4 liver
conjug metab + excreted renally
midazolam also cyp
Morphine
bioavail
25%
pka 7.9
unI plasma 23%
plasma prot bind 35%
Vd 3.5
clearnace 16mlkg
30% M6G
can accum in RF - can acumm in rf
IV morphine to po to oxy po to fent 50mcg.h tramadol codeine
3mg PO morph = 1mg IV
Diamorph 3mg sc - 3mg iv
oxy po 6 - 2mg IV
fent 50mcg - 60mg /24
tramadol 100 - 5mg iv
codeine 60 = 2mg iv
Most specific cox 2
lumiracoxib
Protein binding
- Alfentanil 90%
- Fentanyl 83%
- Remi 70%
- Pethidine 60%
albmuin al acid - Morphine 35%
Clearance times
ml . min . kg
Alfentanil 6
Pethidine 12
Fentanyl 13
Morphine 16
Remi 40
if a patient is on PO opiates
safest stop and give iv + pca
eabsorp unred early post op
