Opioids + Analgesia

Question 1

Methadone

Answer 1

• 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

Question 2

Tapentadol

Answer 2

• 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

Question 3

Tramadol

Answer 3

• 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

Question 4

Pethidine

Answer 4

• 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

Question 5

Hydromorphone

Answer 5

• 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

Question 6

Buprenorphine

Answer 6

• 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

Question 7

Fentanyl

Answer 7

• 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

Question 8

Remifentanil

Answer 8

• 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

Question 9

Alfentanil

Answer 9

• 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

Question 10

Morphine

Answer 10

• 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

Question 11

Oxycodone

Answer 11

• 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

Question 12

Codeine

Answer 12

• 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

Question 13

Opioid receptors

Answer 13

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)

Question 14

Opioid MoA

Answer 14

• 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

Question 15

Opioid PK

Answer 15

• 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

Question 16

Prostaglandin synthesis

Answer 16

Phospholipids -> Arachidonic acid (via Phospholipase A)

Arachidonic acid -> Leukotrienes (via lipooxygenase)

Arachidonic acid -> Prostaglandins + thromboxanes (via cyclooxygenase (COX))

Question 17

Paracetamol

Answer 17

• 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

Question 18

Paracetamol OD

Answer 18

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)

Question 19

Aspirin

Answer 19

• 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

Question 20

Aspirin OD

Answer 20

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

Question 21

NSAIDs PK + PD

Answer 21

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

Question 22

Specific COX-2 inhibitors pros + cons

Answer 22

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

Question 23

Parecoxib

Answer 23

• 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

Question 24

Ibuprofen

Answer 24

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

Question 25

Clonidine

Answer 25

• Aniline derivative
• Clear, colourless solution
• Dose 50-300mcg Q6hrly PO/ IV, 15-30mcg intrathecal/ epidural
• MoA - central a2-agonist (a2:a1 ratio 200:1), clonidine is partial agonist. High density in pontine locus caeruleus - decr SNS outflow, sedation. Inhibition of medullary vasomotor centre (spinal cord - modulate descending pain pathways -> analgesia). Peripheral a1 agonists - vasoconstriction

PK
- A - rapidly absorbed with 100% bioavailability PO
- D - Very lipid soluble, easily crosses BBB, 20% protein bound, VD 2L/kg
- M/E - less than half metabolised to inactive metabolites in liver, 65% excreted unchanged in urine, 20% in faeces, Cl 2-4ml/min/kg. Elimination T1/2 6-23hrs (markedly incr in renal impairment, not removed by HD)

CNS
- Analgesic
- Anxiolytic
- Sedating (MAC sparing, depressant effect on sympathetic outflow and somatic reflexes)
- Reduced CBF and CMRO2

CVS
- Transient incr BP (a1) -> sustained decr
- HR and VR may decrease slightly
- CO maintained
- May prolong PR interval
- Coronary vasodilation

GIT
- Decr gastric and bowel motility
- Antisialagogue/ dry mouth

Other
- Reduced PONV and shivering
- Reduces propofol dose
- Obtunds tourniquet induced HTN
- Reduces post-op agitation in children having volatile
- Prolongs duration of LA for neural or orbital block
- Rapid withdrawal can lead to rebound HTN and tachycardia
- Reduced ADH and insulin

Question 26

Agent types for pain management

Answer 26

• Opioids
• LAs
• NSAIDs
• NMDA antagonists
• Anticonvulsants
• Antidepressants
• Corticosteroids
• Inhalational agents

Question 27

Antidepressants

Answer 27

TCA - amitriptyline, notriptyline
Tetracyclic - mirtazapine
SSRI - fluoxetine, paroxetine, sertraline
SNRI - venlafaxine
MAOi - phenelzine, moclobemide, selegiline

Question 28

TCA

Answer 28

E.g amitriptyline, nortriptyline

Mechanism
- Inhibit neuronal reuptake of NA and 5-HT (mechanism of analgesia - increase descending inhibition)
- Antagonist activity at - muscarinic AChR, H1 and H2, a1, NMDA receptors

S/E
- Sedation
- Anticholinergic effects - dry mouth, blurred vision, constipation, urinary retention
- Postural hypotension
- Sinus tachycardia
- Dysrhythmias
- Prolonged QT interval
- Resp depression in toxicity
- Sexual dysfunction
- Lowers seizure threshold

Drug interactions
- Sympathomimetics - unpredictable BP response, arrhythmias
- Anticholinergics - central anticholinergic syndrome
- Tramadol - seizures and serotonin syndrome
- TCA + BDZ + flumazenil - seizures

Question 29

SSRIs

Answer 29

E.g fluoxetine, paroxetine, sertraline

Mechanism
- Inhibit neuronal re-uptake of 5-HT

Comparison to TCA
- Similar anti-depressant effect
- Less sedation
- Fewer anticholinergic effects
- Less cardiotoxic in OD
- More likely to cause sexual dysfunction
- Higher incidence of GIT s/e (e.g nausea)

Drug interactions
Serotonin syndrome
- Mechanism - excessive serotonin activity at CNS and peripheral 5HT receptos
- Triggers - SSRI + MAOi/ TCA/ pethidine/ tramadol
- Signs - rapid onset, cognitive (confusion, agitation, hallucinations), autonomic (sweating, hyperthermic, incr BP + HR), somatic (hyper-reflexia, myoclonus, tremor)
- Tx - discontinue precipitants, supportive in ICU (BDZs, direct acting inotropes, short acting antiHTN)

SSRIs are hepatic enzyme inhibitors.

Question 30

MAOIs

Answer 30

Types
- Non-selective irreversible MAO-A and MAO-B, e.g phenelzine
- Selective reversible MAO-A (RIMA), e.g moclobemide
- Selective irreversible MAO-B, e.g selegiline

Mechanism
- MAO-A deaminates 5HT, NA and dopamine
- MAO-B deaminates dopamine, tyramine and phenyl-ethylamine

Drug interactions
- MAOI + pethidine -> serotonin syndrome (HTN crisis)
- MAOI + SSRI -> serotonin syndrome
- MAOI + indirectly acting sympathomimetic -> HTN crisis and arrhythmias
- MAOI + tyramine rich food -> HTN crisis
- MAOIs are hepatic enzyme inhibitors
- Phenelzine inhibits plasma cholinesterase

Question 31

Anticonvulsant types

Answer 31

• Benzos - midaz, diaz
• Barbiturates - phenobarbital, thiopental
• Salts of carboxylic acid - sodium valproate
• Hydantoins - phenytoin
• Imino-stilbenes - carbamazepine
• Succinimide - ethosuximide
• GABA analogues - gabapentin, pregabalin
• Triazines - lamotrigine

Question 32

Gabapentin

Answer 32

• Structural analogue of GABA
• No direct action of GABAA receptors
• Interacts with a2-delta subunit of voltage gated Ca2+ channels in CNS, inhibits VGCC insertion into cell membrane -> less NT released with incoming AP. Enhanced descending inhibition to the dorsal horn of spine cord. Inhibition of excitatory NT (glutamate).
• Dose - start with 100-300mg Q8hrly, uptitrate to 2000-3600mg daily over weeks. Requires gradual withdrawal of tx

PK
- A - slow absorption, PO availability (30-60%) - inversely related to dose
- D - no plasma protein binding
- M - negligible metabolism
- E - excreted unchained in urine, dose reduction in renal impairment. T1/2 6hrs, Cl reduced in elderly

PD
- Analgesia - modulates pain pathway under pathophysiologic conditions
- Adverse effects - sedation, dizziness, fatigue, ataxia, nausea, withdrawal syndrome, risk of increasing opioid induced resp depression in elderly

Question 33

Pregabalin

Answer 33

• Structural analogue of GABA
• No direct action of GABAA receptors
• Interacts with a2-delta subunit of voltage gated Ca2+ channels in CNS, inhibits VGCC insertion into cell membrane -> less NT released with incoming AP. Enhanced descending inhibition to the dorsal horn of spine cord. Inhibition of excitatory NT (glutamate).
• Dose - 50mg PO BD Q8hr, increase gradually to max 200mg PO Q8hrly

PK
- A - rapid absorption, PO availability 90%
- M - negligible metabolism
- E - excreted unchained in urine, dose reduction in renal impairment. T1/2 6hrs

PD
- Analgesia - modulates pain pathway under pathophysiologic conditions
- Adverse effects - dizziness, dry mouth, sedation, blurred vision, weight gain, nausea

Question 34

Corticosteroids

Answer 34

Mechanism
- Transactivation - binds glucocorticoid receptor, translocates to nucleus and activates transcription of proteins. Anti-inflammatory mediators, gluconeogenesis
- Transrepression - binds GC receptors, translocates to uncles and prevent transcription of proteins. Reduce NFkB
- Non-genomic - direct activation of mRNA - reduces activation of arachidonic acid and is anti-inflammatory

Effects
- Anti-inflammatory - increases production of lipocortin which reduces PLA2; thus reduces production of mediators down arachidonic acid pathway - PGs, LTs. Reduced chemotaxis
- Anti-insulin - incr glycogenolysis and gluconeogenesis. Incr protein catabolism. Incr lipolysis
- Immunosuppression - depression of macrophage function, reduce number of circulating T-cells, reduced Ab production, incr risk of infection
- Anti-emetic - via CNS GC receptor
- Weak mineralocorticoid activity - act on DCT to incr Na and water retention - can cause oedema. Hypokalaemia, HTN
- Peptic ulcer - reduce PG synthesis - incr gastric acid and pepsin secretion
- Haematological - leukocytosis, mild incr RBC
- Adrenal suppression - negative feedback on hypothalamus release of ACTH; see atrophy of adrenal gland
- Vascular reactivity - synergism with catecholamines, incr response to catecholamines
- Osteoporosis
- Poor wound healing
- Psychiatric - can induce psychosis/ delirium
- Growth suppression in children

Question 35

Naloxone

Answer 35

PC
- N-alkyl derivative of oxymorphone
- Weak base, pKa 8
- Dosing 40mcg -2mg
- Can be given IM and SC at higher doses

PK
- A - 2% PO BA, useful given PO to offset some GI S/E of opioids
- D - onset 2min, rapid redistribution so fast offset ~20mins. 46% PPB, VD 2L/kg
- M - rapidly metabolised in liver with very high Cl (30ml/kg) -> naloxone-3-glucuronide. Offset faster than most opioids so need repeat dosing or infusion
- E - terminal T1/2 1-2hrs

PD
- Competitive antagonist of all opioid receptors (MOP>KOP=DOP 3:2:2)
Prevents activation of GiPCR -> incr GC -> incr cAMP -> incr activity VDCC + decr K+ efflux -> facilitate depolarisastion
- No PD effect in absence of opioids
- Pain
- Acute withdrawal syndrome, N+V, seizures
- CNS - pain, anxiety, agitation, seizure
- CVS - incr SNS output, tachycardia, HTN, arrhythmia, APO