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
