Opioids + Analgesia Flashcards
Methadone
- Synthetic opioid
- Full agonist at MOP, KOP, DOP
- NMDA receptor antagonist
- Inhibits reuptake of serotonin and NA
- Racemic mixture of 2 enantiomer - L-methadone (opioid agnostic), D-methadone (NMDA antagonist, NA and 5HT)
- A - PO bioavailability 75% (low first pass metabolism)
- D - Protein binding 90%, large VD 300L
- M - Hepatic metabolism to inactive metabolites via CYP2D6
- E - 40% excreted unchanged in urine; longest T1/2B 50hrs (long acting so development of acute withdrawal less likely)
Other
- Less sedative than morphine
- May cause QT interval prolongation with large doses
- High inter-individual variability
- Uses in chronic pain, opioid abuse and withdrawal, acute pain periop
Tapentadol
- Opioid and non-opioid action in single non-racemic molecule - MOP receptor agonist, blocks reuptake of NA in brain
- A - PO bioavailability 30%
- D - Onset 30mins PO, offset 4-6hrs
- M - Hepatic metabolism (no active metabolites)
- E - Renal excretion, T1/2B 240mins
Other
- 2-3x less potent than morphine, more potent than tramadol
- Improved S/E profile compared with other opioid agonists
- Tapentadol + MAOIs -> potential for hypertensive crisis and arrhythmias
Tramadol
- Racemic mixture of 2 enantiomers
=> (+)S-tramadol - MOP agonist and 5HT reuptake inhibition. (-)R-tramadol - responsible for NA reuptake inhibition - Weak opioid receptor agonist
- Non-opioid = blocks reuptake of NA + 5HT, stimulates presynaptic 5HT release; NMDA receptor antagonist
- pKa 9.4, crosses placenta
- A - PO bioavailability 80%
- D - 20% protein bound; VD 4L/kg; crosses placenta
- M - Hepatic CYP2D6 demethylation -> glucuronidation; O-desmethyl-tramadol (M1) - 6x more potent than tramadol. Genetic polymorphism. CYP3A4 to M2
- E - really excreted; T1/2B 300mins
Other
- 10x less potent than morphine
- Less sedation, resp depression, constipation, dependence
- Lowers seizure threshold
- Anti-shivering
- Interactions - risk of serotonin syndrome with MAOI, SSRI, TCAs or other serotonergic meds
Naloxone only reverses 30% of analgesic activity (as remainder from SSRI/ SNRI effect)
Ondansetron can diminish/ reverse analgesic effect
Pethidine
- Synthetic opioid
- MOP and KOP agonist, inhibits pre-synaptic 5HT and NA reuptake
- Tablets, clear colourless liquid
- 30x more lipid soluble than morphine
- pKa 8.5 (<10% unionised at pH 7.4)
- A - PO bioavailability 50%
- D - protein binding 70%, VD 4L/kg, crosses placenta
- M - hepatic metabolism
=> De-methylation to norpethidine (90%) (50% potency), marked convulsant properties, long T1/2 12-24hrs
=> Ester hydrolysis to pethidinic acid (inactive) - E - renally excreted, T1/2B 200mins
Other
- 10x less potent that morphine
- LA activity
- Anti-shivering
- Lowers seizure threshold
- More potent ventilatory depressant than morphine
- Atropine-lie effect (dry mouth, tachycardia, less mydriasis)
- Addictive potential
- Myocardial depressant at high doses
- Interaction with MAOI -> serotonin syndrome (hypertensive crisis), central pethidine inhibition of serotonin reuptake, MAOI-induced reduction in amine breakdown
- Onset of action IV <1min
- Peak effect IV 5-20mins
Hydromorphone
- Semisynthetic opioid
- High lipid solubility than morphine (better BBB penetration, more rapid onset)
- A - poor PO bioavailability 30%
- D - 10% protein bound;VD 4L/kg
- M - Hepatic metabolism -> hydromorphone-3-glucuronide (inactive)
- E - Renal excretion; T1/2B = 120mins
Other
- 5x more potent than morphine PO
- 9x more potent than morphine IV
- Hydrophilic (epidural) - once daily formulation
- More expensive than morphine
Buprenorphine
- Semisynthetic opioid
- Clear colourless solution - transdermal, SL, IV
- Partial MOP receptor agonist (high affinity, dissociates very slowly, prolonged analgesia up to 10hrs)
- KOP receptor antagonist (KOP effects predominate with incr doses -> anti-analgesic effect)
- A - PO bioavailability 50% - sig first pass metabolism
- D - 96% protein bound, VD 3.2L/kg
- M - Hepatic metabolism CYP3A4 to norbuprenorphine (active)
- E - Biliary and renal excretion; T1/2B = 40hrs
Other
- 25x more potent than morphine
- not completely reversed even after large doses of naloxone
- Decr risk of resp depression (ceiling effect)
- Analgesia with less euphoria
Fentanyl
- Synthetic phenylpiperdine derivate - racemic mixture
- pKa 8.4 (<10% unionised at pH 7.4)
- A - PO bioavailability 30%
- D - 600x more lipid soluble than morphine (rapid onset), DoA 30-60mins due to rapid redistribution; 85% protein bound; VD 4L/kg; significant first pass pulmonary endothelium uptake (75%)
- M - Hepatic N-dealkylation by CYP3A4 to norfentanyl (99%, clinically inactive), hydroxylation of both parent compound and norfentanyl
- E - renal excretion, T1/2B = 190mins; long CSHT
Other
- 100x more potent than morphine
- HD stability
- Muscle rigidity at high doses
- Nil sig histamine release
- Facial itching
- Onset after IV <30s
- Peak effect after IV 3-5mins
Remifentanil
- Synthetic phenypiperdine derivative of fentanyl
- White lyophilised power with a glycine buffer (not for intrathecal)
- pKa 7.3 (58% unionised at pH 7.4)
- 20x more lipid soluble than morphine (less than fent and alf)
- D - protein binding 70% to alpha1-acid glycoprotein; VD 0.4L/kg;
- M - Ester hydrolysis by non-specific plasma and tissue esterases; carboxylic acid metabolic (inactive)
- E - 95% renal excretion; T1/2B 10mins; CSHT fixed 3-5mins
Other
- Similar potency to that of fentanyl
- No histamine release
- Associated with post-infusion hyperalgesia
- Dose 1-2mcg/kg/bolus, 0.1-0.5mcg/kg/min infusion (Use LBW for obese)
- Peak effect at 90s
Alfentanil
- Synthetic opioid
- 90x more lipid soluble than morphine
- pKa 6.5 (90% unionised at pH 7.4)
- Dose 10mcg/kg bolus, 0.5-1mcg/kg/min infusion
- D - 90% protein bound; VD 0.6L/kg
- M - hepatic N-dealkylation by CYP3A4 -> noralfentanil
- E - renal excretion; T1/2B 100mins
Other
- 10-20x more potent than morphine
- Nil sig histamine release
- Onset of action IV <30s
- Peak effect after IV 1-2mins
Morphine
- Natural opioid, phenanthrene derivative
- Relatively lipid soluble (crosses BBB slowly -> slower onset of action)
- pKa 8 (23% unionised at pH 7.4)
- A - PO availability 25% - extensive first pass metabolism
- D - protein binding 35% to albumin; VD 3.5L/kg
- M - hepatic glucuronidation (phase II) to 70% M3G (inactive) and 10% M6G (active - 15x more potent than morphine); also demethylation (phase I) to normorphine (5%)
- E - Renal elimination; T1/2B 1.7-4.5hrs
Other
- M3G has adverse if acculumulates despite inactive
- Onset of action after IV <1min
- Peak effect after IV ~15mins
Oxycodone
- Semisynthetic opioid
- pKa 8.5 (<10% unionised at pH 7.4)
- Lipid solubility similar to morphine
- Dose 0.1mg/kg bolus, PO 5mg Q4hrly
- A - PO bioavailability 70%
- D - 45% protein bound; VD 2.6L
- M - Hepatically metabolised by O-demethylation by CYP3A4 to noroxycodone and CYP2D6 to oxymorphone (15%) (14x more potent)
- E - renal excretion, T1/2B 200mins
Other
- Onset of action PO 10-15mins, IV 2-3mins
- 1.5x more potent than morphine
Codeine
- Natural opioid
- Methylated morphine derivative
- Prodrug
- A - PO bioavailability 60-70% with min first pass metabolism
- D - 7% plasma protein bound; VD 5.4L/kg
- M - Hepatic CYP2D6 - Glucuronidation, de-methylation (to norcodeine + morphine (10% dose); genetic polymorphism (poor metabolisers -> little analgesia)
- E - renally excreted; T1/2B 160mins
Other
- 10x less potent than morphine
- Onset of action after PO 15-30mins
Opioid receptors
All opioid receptors are Gi
MOP (1, 2)
=> Locations - PAG, RVLM, NRM, thalamus, hypothalamus, cortex, dorsal horn
=> Most opioid effects
=> Analgesia (spinal and brain) - incr descending modulation (brain), decr ascending nociceptive signal (spine)
=> Euphoria
=> Miosis (via stimulation of Edinger-Westphal nucleus)
=> N+V (via CTZ)
=> Sedation
=> Bradycardia
=> Inhibition of gut motility -> Constipation
=> Urinary retention
=> Physical dependence
(Only opioid receptor to cause N+V)
KOP
=> Analgesia (predominantly spinal)
=> Sedation
=> Miosis
=> Dysphoria
(Less resp depression)
DOP
=> Analgesia
=> Resp depression (decr central chemoreceptor sensitivity to CO2)
=> Urinary retention
=> Physical dependence
(Minimal constipation)
NOP: role unclear
=> Anxiety, depression
=> Change in appetite
(Hyperalgesia at low doses, analgesic at high doses)
Opioid MoA
- Gi protein coupled receptors
- Inhibit adenylate cyclase -> decr cAMP
- Presynaptically inhibits voltage gated Ca2+ channels -> decr Ca2+ influx -> inhibition of neurotransmitter release (e.g substance P)
- Post-synaptically activates K+ channels -> incr K+ efflux -> hyper polarisation -> decr neuronal excitability
Opioid PK
- Highly lipid soluble weak bases
- High protein bound
- Largely ionised at physiologic pH (except remi and alf- largely unionised)
- Metabolised in liver by CYP450 (except remifentanil - hydrolysed by plasma esterase’s hence rapid organ independent elimination)
- CYP3A4 metabolises fentanyl and alfentanil
Prostaglandin synthesis
Phospholipids -> Arachidonic acid (via Phospholipase A)
Arachidonic acid -> Leukotrienes (via lipooxygenase)
Arachidonic acid -> Prostaglandins + thromboxanes (via cyclooxygenase (COX))
Paracetamol
- Para-aminophenol
- Weak acid, pKa 9.5 (nearly completed unionised)
- MoA - unclear. COX-3 (COX-1 variant) inhibitor in CNS -> antipyretic effect. No inhibition of peripheral COX activity. 5HT1B agonist -> analgesia (possible antagonised by 5HT3 antagonists).
PK
- A - PO bioavailability 80%. Heavily dependent on factors such as rate of gastric emptying, pH and formulation
- D - 10% plasma protein binding (20% in OD), distributed throughout body with rapid elimination due to low protein binding, lipid soluble. VD 1L/kg larger than other NSAIDs due to lipid solubility and low protein binding
- M - Hepatic metabolism, 80% to conjugates (glucuronidation and sulfation), 10% oxidised by CYP2E1 to NAPQI (highly toxic), rapidly conjugated with glutathione to inactive compound
- E - 90% of paracetamol or metabolites excreted in urine. T1/2 120mins
Effects
- Analgesic (synergy with NSAIDs, opioid sparing, role in multimodal analgesia)
- Anti-pyretic
- Little anti-inflammatory effects
- Rare effects - GIT upset, rashes, thrombocytopenia, leukopenia, neutropenia
Paracetamol OD
Recommended dose
- Children - PO loading 20mg/kg, maintenance 15mg/kg Q4-6hr
=> IV (48hrs) - no loading, <10kg 7.5mg/kg Q6hr, >10kg 15mg/kg Q6hr
Fatal dose
- Single dose >10g or 200mg/kg body weight whichever is lower
Risk factors
- Chronic alcohol intake
- Fasting or anorexia nervosa - depletion of hepatic glutathione stores
- Hepatic enzyme induction
- Elderly
Mechanism
- Depletion of glutathione stores -> accumulation of NAPQI -> hepatocyte necrosis
Features
- N+V
- Epigastric/ RUQ pain
- LFTs deranged >18hrs post ingestion
- Late (3-4days) - signs of severe liver failure (hypoglycaemia, encephalopathy, cerebral oedema, lactic acidosis)
- 10% develop ATN
Management
- Activated charcoal (if early post ingestion)
- Restoration of glutathione stores - PO methionine (enhances glutathione synthesis), IV N-acetyl-cysteine (hydrolysed to cysteine, glutathione precursor)
- Refer to specialist centre
- Liver transplant (INR >5, metabolic acidosis, hypoglycaemia, renal failure)
Aspirin
- Salicylate
- Weak acid
- pKa 3 - mostly ionised at physiological pH, mostly unionised in stomach. Absorbed in stomach but mostly in small intestine (larger SA) - mucosal cells are relatively alkaline -> ion trapping -> aspirin does not reach systemic circulation
- Aspirin itself is active, but also metabolised to salicylate which is also active
- Cross-reacts with other NSAIDs -> basis for NSAID-induced asthma
- MoA - irreversible COX inhibitor -> decr synthesis of PGs -> analgesic, anti-inflammatory and anti-pyretic effects.
=> Decr synthesis of TXA2 in platelets -> antithrombotic effect (COX-1)
=> Uncouples oxidative phosphorylation (incr O2 consumption and CO2 production)
PK
- A - PO bioavailability 70%, rapidly absorbed, undergoes high degree of pre systemic hydrolysis by intestinal and hepatic esterases to form salicylate prior to absorption
- D - salicylate 85% protein bound, VD 10L, limited ability to cross BBB
- M/E - rapidly hydrolysed by nonspecific esterases into salicylate (within 15-20mins absorption), salicylate and its metabolites excreted by renal elimination (70% metabolised via saturable pathway, hence zero order kinetics at high doses). Plasma T1/2 of salicylate after low dose aspirin 2-3hrs cf 15-30hrs after high doses
Effects
- General NSAID effects
- Reye’s syndrome
=> Fatty liver
=> Encephalopathy
=> Cerebral oedema
=> Contraindicated in children <16yrs
Adverse
- COX1 - bleeding, GI ulceration, nephrotoxicity (not at antiplatelet doses)
- COX2 - prolonged labour
Aspirin OD
Overdose
- 150-300mg/kg = mild-mod
- >300mg/kg = severe
Mechanism
- Uncouples oxidative phosphorylation -> incr O2 consumption and incr CO2 production -> hyperventilation
- Incr aspirin levels -> direct stimulation of resp centre -> resp alkalosis
- Metabolic acidosis
- Children - mixed resp and metabolic acidosis, rising aspirin levels -> depression of resp centre
Features
- Sweating
- Tinnitus
- Blurred vision
- Tachycardia
- Pyrexia
- Hyperventilation
- Complication - seizure, cerebral oedema, pulm oedema, cardiac arrest
Treatment
- Activated charcoal
- Forced alkaline diuresis
- HD
NSAIDs PK + PD
PK
- A - good PO absorption, generally rapid
- D - highly plasma protein bound limiting distribution to extravascular space, VD often very low (except paracetamol)
- M - hepatic metabolism to inactive metabolites via CYP
- E - renal elimination
PD
COX inhibition and reduced PG synthesis
- Analgesia
- Anti-pyretic
- Anti-inflammatory
Platelet anti-aggregation
- Reduced TXA2 for non-specific NSAIDs due to COX-1 inhbition
- COX-2 inhibitors have little effect
- Low dose aspirin exposed only to platelets and bind them
GIT
- Non-selective - increase risk of peptic ulcers/ perforation/ GIB (not seen with COX-2)
- Due to reduced mucous secretion in stomach and reduced local blood flow
Renal
- Renal impairment due to inhibition of PG mediated vasodilation - hypo perfusion and decr GFR (COX 2 involved in water and electrolyte homeostasis, COX 1 involved in renal haemodynamic regulation and GFR)
- Transient Na + water retention - oedema
- Chronic aspirin -> acute interstitial nephritis
Resp
- May worsen asthma in 10-20% asthmatics - reduced PG synthesis leaves more AA available for leukotriene synthesis via 5-lipooxygenase pathway resulting in bronchospasm (mainly COX-1)
CVS
- COX-2 specific increase risk of thrombotic events - contraindicated post cardiac surgery
- Prolonged COX-2 increases risk of CVS adverse events - MI, CVA
Others
- Bone healing ?impaired
- Hepatotoxicity - resolves 4-6 weeks post cessation
- Tocolytic
- Closure of DA - fetal asphyxia
- Hyperkalaemia
- May displace other drugs from plasma protein binding sites - heparin, warfarin
- Allergy - sulphur containing compounds
Specific COX-2 inhibitors pros + cons
Advantages
- Decr peptic ulcer and GIT bleeding
- Decr postop bleeding
- No effect on plt function
- Less likely to cause bronchospasm
- Better theoretical anti-inflammatory effect
Disadvantages
- Expensive
- Concerns about CVS safety
- Similar risk of renal impairment
Parecoxib
- Specific COX-2 inhibitor
- Prodrug of valdecoxib
=> COX-1:COX-2 inhibitory ratio 1:60 - Dose 40mg IV, followed by 20-40mg Q6-12hrly, max 80mg/day not approved in children
- Onset within 15mins IV, peak effect within 2hrs IV
- D - reaches Cmax within 30mins after injection, rapidly hydrolysed to valdexocib with Cmax valdecoxib 1hr. 97% plasma protein bound to albumin
- M/ E - rapidly hydrolysed to valdexocib to CYP2C9 and CYP3A4. Valdexocib undergoes extensive metabolism to multiple metabolites
T1/2 B parecoxib 20mins, valdexocib 8hrs - Potent analgesic
- Rare S/E - in pts who also have sulphonamide sensitivity, SJS, angioedema
Ibuprofen
Propionic acid
A - rapid and near complete >80% from FIT
- S-enantiomer is the active component, R-enantiomer undergoes transformation into S
- Longer ibuprofen remains in GIT = more likely pre systemic conversion occurs = increasing S:R enantiomer ratio
- Also systemic enantiomer conversion
D - 99% protein bound
M/E
- Metabolised by liver to adenylate, glucuronidate, hydroxyl or carboxyl derivative
- 60% excreted as hydroxyl or carboxyl conjugates
- <1% excreted unchanged in urine
