14. Analgesia Flashcards
How does clonidine work?
Alpha 2 adrenergic receptor agonist that causes pre-synaptic re-uptake of norad
If works peripherally.
Central causes analgesia at alpha 2 in substantial gelatinisation of cord
Less resp depression and N&V than opiates but more sedation and hypotension
What kind of drug is paracetamol?
How does it work?
Atypical nsaid
Inhibits cox 1 and 2 and therefore prostaglandin synthesis
Increased cannabinoid receptor activation
Inhibits descending serotenergic pathways
Analgesic and antipyretic
What can paracetamol be useful for pre-op?
Given 1h prior to op, can stop central sensitisation
What is the onset time, peak and duration of paracetamol IV and oral?
IV = 5min, peak in 40-60 and lasts 6h
Oral = onset 40m, peak 1-2h
How is paracetamol excreted?
Renal
What are the toxic doses of paracetamol OD?
What is the treatment?
S/E?
Potential hepatic injury at over 10g in over 50kg and over 150mg/kg in under 24h in under 50kg
Over 800mg/l can cause coma or lactic acidosis
Gastric decontamination within 1h
100% survival if NAC within 8h - hydrolysed to cysteine intracellularly to replenish glutathione stores
S/E: rash, N&V, angioedema, flushing, tachy, bronchospasm and hypotension
What is the mechanism of aspirin?
Irreversible non-selective cox inhibitor.
Inhibits prostaglandin production, prostacyclins and thromboxane
What is the pathway of prostaglandin synthesis?
What drugs interact with the different steps?
What are the final products?
Essential fatty acids —> membrane phospholipids
Phospholipase A2 converts this to arachidonic acid (blocked by steroids)
Arachidonic acid can either be converted to leukotrines by lipoxygenase or to prostaglandin H2 by cox (inhibited by NSAIDs.
H2 makes:
Prostacyclin (vascular endothelium): increases platelet camp, but reduces activation and causes vasodilation
Prostaglandins (everywhere): smooth muscle control, inhibit gastric acid, hyperalgesia and renin release
Thromboxane A2 (platelets): increased platelets, aggregation and vasoconstriction
What do NSAIDs cause bronchospasm?
How many people does this effect?
Preventing formation of prostaglandin H2 causes arachidonic acid to go down other pathway to make leukotrienes
Effects 10-20%
What are the selective and non selective NSAIDs?
Non = aspirin, diclofenac, ketorolac and ibuprofen
Selective = parecoxib
What are the good and bad effects of aspirin?
Analgesia
N&V (stimulates CTZ)
Respiratory alkalosis
Metabolic acidosis
Blood sugar reduced at low doses and increased at high doses
What is the metabolism and excretion of aspirin?
Rapidly metabolised by hepatic and intestinal esterases to form salicylate. Then various pathways in the liver. Two become saturated at low doses, changing from first to 0 order kinetics.
Renally excreted
What are the toxic levels of aspirin?
The effects?
The treatment?
Poisoning signs at 40-50mg/dl (2.9-3.6mmol)
Death at over 10g and 3 in kids
Mild = under 500mg/L
Moderate 500-750
Severe = over 750
See respiratory alkalosis or mixed. Alkalosis traps salicylate anions in the blood (avoid intubation or give high MV). Glucose, Coag abnormalities and AKI
Needs repeated level measurements
Charcoal in under 1h
Correct electrolytes
Vit K if prolonged PT
Glucose normalisation
Bicarbonate (2h K levels if giving this) for acidosis and urinary alkalinization
Haemodialysis if severe
What are the cox’s and where is each found/do?
Isoenzymes of each other.
Cox 1: Stomach = gastroprotection, renal = Na and water balance, platelets = aggregation
Cox 2: normally in brain, kidney, ovary and uterus (contributes to embryo implantation and labour)
Can be induced to be involved in: inflammation, pain and fever.
Cox 3: splice variant, thought to be involved in central pain.
Do we usually use selective cox 2 inhibitors?
No most have been withdrawn due to higher risk of VTE
What are the different routes for NSAIDs and what drugs use each?
IV = ketorolac and parecoxib
Diclofenac: oral, IV or PR
Rest oral
What are the general kinetic features of NSAIDs and interactions?
A: weak acid so rapid upper GI absorption
D: highly protein bound, can displace other protein bound e.g. morphine and phenytoin
M: high oral BA due to lower first pass
E: renal
Interact with methotrexate and lithium
When are NSAIDs used with caution?
Pre-eclampsia
Pregnancy
Surgeries with high bleeding or bleeding risk
Co-morbidities
No aspirin in kids (Reyes)
No increased risk with regional
What is opium?
Mix of alkaloids from papaver sominferum opium poppy juice
What are the difference between opiates and opioids?
Opiates are naturally occurring
Opioids are natural or synthetic with morphine like properties
What is a narcotic?
Narco is Greek for numb
Drugs with analgesic and sedative properties
Where are endogenous opioids mostly found?
Hypothalamus, pituitary, periductal aqua grey, brain stem and substantial gelatinosa
Also some peripheral
What are the three main categories of endogenous opiates?
Receptors?
Effects?
Endorphins: hypothalamus and pituitary. Predominantly Mu with some delta. Give analgesia and euphoria
Enkephalins: predominantly delta, some mu. Nociception
Dynorphins: kappa receptors. Analgesia, appetition regulation and circadian rhythm
What type of receptors are opiate receptors and what are the three main types?
All GCPR
Mu, delta and kappa
What’re are mu receptors found?
Main agonists?
Antagonists?
Effects?
CNS and GI tract
Agonists: opioids and buprenorphine
Antagonists: nalpuphine and nalorphine (these are agonist antagonists as they agonise kappa receptors - antagonise morphine, but activate kappa, so if given at same time, they put a ceiling on morphine analgesia and respiratory depression). Also naloxone
Effects: analgesia, dependence, euphoria, respiratory depression etc (think IVDU)
What’re are delta receptors found?
Main agonists?
Antagonists?
Effects?
Olfactory bulb, cerebral cortex, nucleus accumbens and caudate putamen
Agonists: none available
Antagonists: naloxone
Effects: analgesia and hormone release
What’re are kappa receptors found?
Main agonists?
Antagonists?
Effects?
CNS
Agonists: morphine, nalorphine and nalbuphine
Antagonists: naloxone and naltrexone
Effects: analgesia, sedation, miosis and higher dysphoria than mu
What is the main mechanism of action of opioids?
Inhibit descending pathways by:
Reduced signalling in substantial gelatinosa
Reduction of neurotransmitter release from pre-synaptic
Hyperpolarisarion of post synaptic reducing AP
Also in peripheral sensory neurones. Inflammation up regulates receptors and causes localised endogenous release of opiates
What is a broad overview of the pain pathway e.g. ascending and descending?
What do opioids do to this?
Peripheral afferent synapses in dorsal horn
Ascending pathway goes up through nucleus raphe to periductal aqua grey in the pons (and to other parts of brain)
GABAergic interneurones reduce activity of descending inhibitory pathways
Opioids inhibit gaba release and so causes disinhibition of these pathways and reduces activity in the afferent nociceptive pathways through norad and 5HT release.
What are the different classification types for opiates?
Source
Receptor affinity
Potency
Family
What are the different source classifications of opioids?
Drugs?
Natural = morphine codeine and thebaine
Semisynthetic (derived from natural sources) = diacetylmorphine (heroin) and hydromorphone from morphine. oxycodone and hydrocodone from codeine and buprenorphine from thebaine.
Synthetic = fentanyl etc.
What are the different receptor affinity classifications of opioids?
Drugs?
Full agonist e.g. fentanyl and morphine and pretty much all the others except below.
Partial: buprenorphine
Antagonists: naloxone
Mixed agonist and antagonist: nalbuphine and nalorphine
What are the respiratory effects of opioids?
Direct suppression of rhythm generation in the venterollateral medulla
Reduced central CO2 sensitivity
Reduced peripheral sensitivity to hypoxia
Cough supression
Chest wall rigidity
What are the CVS effects of opioids?
Brady and hypotension due to decreased sympathetic tone
Anaphylaxis and peripheral vasodilation due to histamine release
What are the neuroendocrine effects of opioids?
Reduced ACTH, prolactin and gnrh secretion
Increased ADH
What are the urinary effects of opioids?
Retention due to increased detector tone and inhibition of voiding reflex
What is the difference between tolerance, dependence and addiction?
Tolerance = decreasing effect to same dose
Dependence = withdrawal on cessation
Addiction is a poly system disease, with a power compulsion to use despite not being medically needed.
What are the 4 different forms of u agonist and drugs?
Morphinans: morphine, codeine etc.
Phenylpiperdines: pethidine, fentanyl and alfentanil
Diphenolpropylamines: methadone
Esters: remi
How did morphine get its name?
Morpheus the Greek god of dreams
What is the metabolism and excretion of morphine?
Glucuronidation in the liver and gut = enterohepatic recirculation
70% morphine 3 glucuronide
Small amount demethylated to normorphine
Rest to M6G which is more potent than morphine (most of pharmacological activity)
All renally excreted so accumulate in CKD
What is diamorphine?
Metabolism?
Semi synthetic : 3,6 diacetylmorphine which is a prodrug with no u receptor activity until metabolised by tissue and plasma esterases to 6-MAM and then morphine
What is papervertum?
Semi synthetic mix of 80% morphine, codeine and papeverine
What is the structure of oxycodone?
What receptor does it work on?
What is the oral BA?
How is it metabolised?
Semi synthetic: codeine molecule with 6-hydroxyl group replaced with a ketone group
Full u agonist
Higher oral bioavailability than morphine at 60%
Predominantly N-demethylation to noroxycodone (weak effect) and small amount to oxymorphone (strong activity)
What is thebaine?
Formulation?
Uses?
Opioids with stimulant effect that can produce convulsants at thigh doses
Natural entantiomer is inactive, but synthetic work on opioid receptors
Not used clinical but is part of oxycodone and naloxone production
What is pethidine and what receptors does it work on?
What is its lipid solubility?
Metabolism and excretion?
What are the bad effects/interactions?
Opioid with u and cholinergic receptor activity
Higher lipid solubility than morphine so faster onset and shorter duration
Phase 1 metabolism to 3 metabolites including norphethidine. Renally eliminated
Interacts with MAOi’s and can cause seizures of accumulates
What happens with one and repeated/high blouses of fentanyl?
One = raid redistribution and 13m half life, but rapid fall to subtherapeutic
Repeated/high = remaining high plasma volume after redistribution so offset dependent on elimination which is slow 3-4h.
How is fentanyl metabolised?
Dealkylated to norfentanyl - inactive
What doses of fentanyl are required to abolish surgical stress response?
What are the side effects of this?
Over 50mcg/kg
Can cause: Brady, hypotension and chest wall rigidity
What ways can we give fentanyl?
Iv
Patch (2 days to steady state)
Lollipop (avoids first pass metabolism)
What is remi derived from and how does its speed and potency compare to fentanyl?
Fentanyl derivative
Similar speed and potency
What is the metabolism and CSHT of remi?
Excretion?
What can boluses causes?
Has two ester links
Metabolised via hydrolysis by tissue and red cell esterases (unaffected by anticholinesterases as not plasma cholinesterases). These aren’t subject to polymorphisms. Broken down to carboxylic acid derivative with 1% potency
Half time post infusion stopping is 5m irrespective of infusion time
Renally excreted
Boluses can cause Brady and hypo and arrest. Need to flush cannula at the end to avoid this.
What is the formulation of tramadol?
What receptors does it work on? What does this mean for naloxone?
Codeine analogue
Racemic mixture of two stereoisomer’s
One is a weak opioid agonist with some u selectivity, but also inhibits neuronal re-uptake of 5-HT
Other inhibits neuronal uptake of norad effecting descending pathways. Partially reversed by naloxone
What are the OD effects of tramadol?
Some Opiate signs e.g. small pupils
Mostly serotonergic and can cause serotonin syndrome
What is the metabolism and excretion of tramadol?
Four different pathways and one having a greater u affinity than parent
Can accumulate in AKI
What is codeine and where does it come from?
What receptors does it cover?
Weak opiate in opium poppy at lower levels than morphine
Works at u but a little bit of delta and kappa
What is the metabolism of codeine and what individual differences are seen?
Pro drug with 10 undergoing o methylation to active metabolite (morphine) and the demethylayed to inactive.
2D6 - rapid metabolisers = OD
9% of white people have a complete absence so no response.
What is DHC?
BA?
Metabolism?
Synthetic codeine derivative
20% oral BA (poor absorption and high first pass)
Metabolised to dihydromorphine and norhydrocone
What is buprenorphine and what receptors does it work on?
What causations must we take when giving it?
Partial u receptor agonist (also KOR and DOR)
Need to make sure other opiates have work off as partial u agonist can have a stronger affinity than other drugs, displacing them and causing withdrawal. Stop 24h before surgery and replace with other drugs.
What is the BA of buprenorphine and routes?
Metabolism and excretion?
Is it reversible by naloxone?
Poor oral BA (30-60%) so given by SL, nasal, transdermal or buccal.
Metabolised to norbuprenorphine (full agonist) and excreted in bile.
Duration of action = 10h so hard to reverse with naloxone
What is naloxone?
What is the receptor affinity?
How is it given and why?
Timings?
What are the side effects?
Competitive opioid receptor antagonist
Predominantly MOR but also DOR and KOR
Low oral BA so IV, IM or nasal
Works in 2m and last 30-45m (elimination HL = 2.5h)
Can cause HTN, arrhythmias and pulmonary oedema
What is naltrexone? What receptors?
How is it given?
Metabolism and excretion?
Uses?
Timings?
Competitive MOR and KOR agonist
High oral but can also give IM or implant
Liver metabolism and renal excretion
Long term management of opioids or alcohol
Works in 30m and HL of 4h active metabolite has a duration of 24h
