6. Analgesics

Question 1

Problems with OSA + Death in paeds w/ codeine

Answer 1

Ultra-rapid metabolisers” are more likely to have higher than normal amounts of morphine in their blood after taking codeine.

Question 2

what sub are derived prepro-opiomelanocortin

Answer 2

Melanocyte stimulating hormone
β-endorphin
Adrenocorticotrophic hormone (ACTH)
β-lipotropin, and
Met-enkephalin

Endog opiod - all peptide - unrelated to lipids (arachadonic acid eg)

Question 3

The action of opioids on the cell is mediated by:

Inhib what channel & where

Inhibits what

Inhib what else

Net effect

Answer 3

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.

Question 4

Canabinoids

Avail PO & Smoke

whats active component

what blocks its action

the production of what is reduced

what do they do to IOP

Answer 4

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).

Question 5

Naloprihne

Pentazocine

Answer 5

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.

Question 6

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

Answer 6

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.

Question 7

NSAID intolerant asthmatics

Answer 7

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.

Question 8

Dorsal horn
what & wheere
modulators

Answer 8

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.

Question 9

Alfentanil is what

Soubility vs fentanyl

Vd
Protein bind
S.E

Why is the onset of Anfentanil qquicker

Answer 9

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

Question 10

Entonox

mix of

effective vs pehtidine

onset max effct

low dose added

side effects for baby?

Answer 10

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

Question 11

NSAIDs renal complications

Answer 11

Reversible renal insufficiency (haemodynamic acute renal failure or kidney injury) is the most common complication of NSAID.

PG syntehsis reduciton - HD insuff

Question 12

Fentayl Dose + response graph

Answer 12

dose and response plotted graphically is a rectangular hyperbola

Question 13

Tramadol

Answer 13

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

Question 14

Papaveretum

Answer 14

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.

Question 15

Remifentanil
is what
acts where

peak effect

metabo by

context sense

release his?

Answer 15

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.

Question 16

Agonists or no at op receptors

Buprenoprhine

Pentazocine

Diamorphine

Naloxone & naltexone

Answer 16

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.

Question 17

Alfentanil

Potency v Fentanyl
why
lipid sol
prot bind

Onset / Offset vs fentanyl - why

Answer 17

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).

Question 18

Fentanyl v Alfentanil

Which is more lipid soluble

When is the onset slower for one of them

Alfent metabolism

High doses of opiod cause

Answer 18

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).

Question 19

Morphine -

Metabolism

End products - %’s

Do they have analgesic property

What other effects do they havehttps://www.brainscape.com/subjects

pka

prot bind

Answer 19

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%

Question 20

Diamorphine

Answer 20

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

Question 21

Pethidine
What is the pethidine metabolite
what does it do

Answer 21

Metab - ester hydolysis - pethidinc acid
N demethylation ->
Norpethidine is a metabolite of pethidine, which is excitatory to the central nervous system.

Norpeth

Question 22

What activity do the alfentanil metabolites have

Answer 22

The metabolites of alfentanil are pharmacologically inactive.

Question 23

Opiate vs Oiod

Answer 23

Opiate - natural occur sub - morphine like prop

Opiod - general - synthetic sub affin for opiod

Question 24

Classification / action / ditsrub receptor

Answer 24

GPCR
CNS, high conc - nuclei tract soilt
periadeq grey
cortex
thalamus

S.cord,
gitm periheral afferent NT

Question 25

Classifcication

Answer 25

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

Question 26

Is the sigma receptor opiod recptor

Answer 26

No not all classic criteria | Naloxone doesnt reveres

Question 27

Mu cuases

Answer 27

Analgesia Miosis euprhoira Mu1 Resp depression braady inhib ghut Preed u2 supra spinal - act brain level Phys - dependence Agonst morphine

Question 28

Delta

Answer 28

analgesia & resp dpression Spinal level Enkpehalin

Question 29

Kappa

Answer 29

``` Sedatio Misois Resp depress Ibnhib ADH - spinal level Ketocylazaine dependewce dif to u ```

Question 30

Opiod level work

Answer 30

presesny gpcr Closs volt Ca Stim K efflux = hyperpol membrane Reduce CAMP Overal reduced cell excitableity Reduction in nocioceptive transmission

Question 31

Routes admin

Answer 31

IV IM PO TDerm , intratehcall,

Question 32

PD effects

Answer 32

``` 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

Question 33

Resp effect opiod

Answer 33

Mu recept brainstem RR fall > TV Reduce paco2 senstivity BStem response to hypoxic stim Antitussive large dose remi - general muscle rigidityy ++ throcic wall

Question 34

Other effects of opioid

Answer 34

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

Question 35

Onset + duration so different | Morphine, fentanyl,

Answer 35

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 ```

Question 36

Morphine metab + excreted

Answer 36

Conjugated M36 - glucorind 700% M6Gluc 10% - active more ptontet than morphine Demtthyal normoprhine 25% Predom excrete urin - conjuagted matob

Question 37

Remi

Answer 37

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

Question 38

S/E

Answer 38

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

Question 39

Nalbphine

Answer 39

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

Question 40

Mode NSAIDs

Answer 40

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

Question 41

Diffrence between cox1 & 2 inhibitors

Answer 41

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 ```

Question 42

NSAID sensitive asthma

Answer 42

20% asthmatics inhibit COX = more arachidonic acid -> leukotrines

Question 43

NSAID & bleeding

Answer 43

Platelt fucntion reduced Txa2 PRevent aggreg vasocn warfarin can be displaced - unpred increased effect (Se li affect random)

Question 44

Ibuprofen

Answer 44

Brfuen Proprionic acid max 1.8g day Paed - 20mg/kg Anti - pyretic, inflamm, anaglesic Lowest inceidence s/e nsaid Elim half 2-3hours

Question 45

Ketorolac &

Answer 45

``` Acetic acid derivate Pteont anglegisc & antipyeritc Lited anti inflamm Side other nsaid Not ci heprain elim half 5 hours 99% ptoein ```

Question 46

Paracetamol

Answer 46

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

Question 47

Paracetamol tox

Answer 47

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

Question 48

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

Answer 48

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.

Question 49

Tapentadol What agonist also acts Active metab?

Answer 49

a MOP receptor agonist and blocks the reuptake of noradrenaline. Unlike tramadol it has not active metabolites.

Question 50

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

Answer 50

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.

Question 51

What are KOR receptors located Where are DOR recptors Where are MOR receptors

Answer 51

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.

Question 52

Enkephalin

Answer 52

Endog pentapeptide proencephalin nerve ending GIT adrenal, medulla t1/2 brain shorter -

Question 53

Fentanyl

Answer 53

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

Question 54

Equiv dose | morpine = diamorphine = oxycodone

Answer 54

Morphine 10 = po Oxycodone 5 = po Diamorphine 3 IM

Question 55

``` alfentanil t1.2 clearance vd pka phys ph *vs remi ```

Answer 55

``` t1.2 elim 100min clear 6ml kg vd 0.6lkg pka 6.5 phys ph 89& union vs remi 68% ``` less clearnce v morphine

Question 56

fentanyl

Answer 56

elim t/12 190 clear 13ml kg vd 4l pka 8.4

Question 57

Pethidine

Answer 57

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

Question 58

Alfentanil - pKa solbil vs fenny metaob where by what what is also - can affect t1/12

Answer 58

6.5 6x less sol cyp3a3/4 liver conjug metab + excreted renally midazolam also cyp

Question 59

Morphine bioavail

Answer 59

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

Question 60

``` IV morphine to po to oxy po to fent 50mcg.h tramadol codeine ```

Answer 60

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

Question 61

Most specific cox 2

Answer 61

lumiracoxib

Question 62

Protein binding

Answer 62

1. Alfentanil 90% 2. Fentanyl 83% 3. Remi 70% 4. Pethidine 60% albmuin al acid 5. Morphine 35%

Question 63

Clearance times

Answer 63

ml . min . kg Alfentanil 6 Pethidine 12 Fentanyl 13 Morphine 16 Remi 40

Question 64

if a patient is on PO opiates

Answer 64

safest stop and give iv + pca | eabsorp unred early post op