Analgesic Drugs Flashcards
Opioid vs opiate
Opioid - acts at opioid receptor
Opiate - derived from opium poppy
Structural classification of opioids
Natural:
Morphine analogues - codeine, morphine
Semi-synthetic
Morphine analogues - diamorphine, dihydrocodeine
Thebaine derivatives - buprenorphine, oxycodone
Synthetic:
Anilinopiperidines - alfentanyl, fentanyl, remi, phenoperidine, sufentany,
Diphenylheptanes - dextropropoxhphene, methadone
Morphinans- levophanol, butorphanol
Phenylpiperdines - pethadine
Types of natural opioids
Phenanthrene (morphine, codiene, thebane - doesn’t do much itself but used for subsequent derivation of oxycodone, naloxone and buprenophine)
Benzylisoquinolines (papaverine, noscopine)
What are the opioid partial agonists and mixed agonist-antagonists?
Effect in patients
Partial - buprenorphine
Mixed - pentazocin, nalbuphine, nalorphine
Provide analgesia in opioid naive but withdrawal in dependant patients
Efficacy of buprenorphine
60-70%
What isomers of opioids exist? Clincial relevance
Opiates - all produced as steriospecific
Synthetic - all racemic
Most cases S are responsible for most clinical effects
Some eg tramadol require both
Rough structure of an opioid and binding
Five rings A-E with A and B in one plane and C and E perpendicular to them
A lies flush to receptor and E fits into a groove in it
Main groups of opioid receptor
MOP - mu
DOP - delta
KOP - kappa
NOP - Orphanin
Effect of MOP receptors
Open potassium channels causing hyperpolarisation and reduced firing
Location of MOP receptors
Primary afferent neurones
Peripheral sensory neurones
Periaquaductal grey matter
Nucleus raphe Magnus
Rostral ventral medulla
Thalamus
Cerebral cortex
Prototype and endogenous agonists at MOP
Prototype - morphine
Natural - leu-enkephalin, met-enkephalin, beta- endorphin
Action at DOP receptors
Potassium channel opening causing hyperpolarisation and decreased neuronal firing
Location of DOP receptors
Olfactory bulb
Cerebral cortex
Primary afferent neurones
Motor integration area
Nociception areas
Prototype and endogenous agonist at DOP
Prototype - ala-leu-enkephalin
Endogenous - leu-enkephalin, met-enkephalin, beta endorphin
Action at KOP receoptors
Directly close calcium channels reducing neurotransmitter release
KOP receptor location
Hypothalamus
Nocicption areas
Prototype and endogenous agonist at KOP
Prototype - ketocyclazocine
Endogenous - dynorphine, beta endorphins
Action of NOP receptors
Directly closing calcium channels reducing neurotransmitter release
Location of NOP receptors
Nucleus raphe Magnus
Primary afferent neurones
Endogenous ligand at NOP
Nociceptin
Orphanin
Structure of an opioid receptor
GPCR
7 transmembrane domains with extracellular n terminus and intracellular c terminus
2nd and 3rd loops responsible for binding.
Have inhibitory action on adenyl cyclase reducing cAMP formation
How do opioid receptors produce stimulatory responses
Inhibition of inhbition
Effect of stimulation of NOP
Clinical implication
Pro nociceptive effect (spinal and supraspinal) or antinociceptive in high concentrations
Thought to be responsible for setting pain thresholds and formation of tolerance.
NOP antagonists produce analgesia and reduce opiate tolerance
MOP and DOP have similar opiate effects all over
What differences do KOP receptors have in their action
Less resp depression
No effect on GI mobility
Dysphoria rather than euphoria
Less sedation or dependence
Cause diuresis
Best beneficial effects of opiates in anaesthesia
Analgesia - best for dull pain
Reduced fear and emotional response to pain
Induce sleep
CNS effects of opiates
Decreased level of consciousness
Sleep
Dose related decrease in MAC for volatiles
Increase cerebral vasoconstriction with vasodilor administration (eg volatiles)
Decreased spinal cord reflexes
Ataxia
Myoclonus (esp pethadine)
Miosis
Decreased thermoregulatory response and decreased BMR
Euphoria
CVS effects of opiates
Preserve cvs stability more than other anaesthetic agents, very little impact in normovolaemic patients
Decrease central sympathetic outflow so can cause cvs depression in already compromised individuals
Morphine causes histamine release which can exacerbate this issue - can be reduced with use of histamine antagonist and volume loading
Effect of pethadine on heart
Tachycardia as homologous with atropine
Significant myocardial depression at high doses
How do opiates effect perioperative mortaility
Reduce stress hormone response associated with pain, laryngoscopy and airway manipulation reducing overall myocardial work, tissue catabolism and hyperglycaemia improving outcomes
Effect of opiates on respiratory function
Decreased rate, Tv,
Pauses, irregular breathing, apnoa
Decreases co2 sensitivity
Decreases airway reflexes
Decreases mucociliary function
Anticough action
GI effects of opiates
Decreas peristalsis,
Decreased secretions
Decreased gastric emptying
Increased pyloric, ileocaecal and anal tone
Increased nausea and vomiting
GI effects of opiates
Antidiueisis due to decreased renal blood flow and decreased GFR
Decreased vasopressin release in response to osmotic stimuli
Increased bladder tone
How common is anaphylaxis to opiatesi
Exceedingly rare!
How does resp depression differ between opiates
Same at equianalgesic dose
Who is most at risk of resp depression from opiates
Neonates and elderly
What could you do in an opiate apnoea patient who is conscious
Ask them to breath!
Voluntary resp control remains intact
Incidence of nausea with opiates
What increases this
What can be done about it
10-60%
Increased in pain free ambulatory patients
Changing opiates may help, as may switching to an oral preparation
What is a major gi side effect of opiates
Constipation that may lead to toxic mega colon in crowns patients
How fast does tolerance develop to gi effects of opiates
Nausea - quickly
Constipation - slowly
What is special about loperamide
Synthetic opiate that doesn’t cross bbb
Effect of opiates on urination
Both urinary retention and urinary urgency
Where is opioid purititus most commonly located
What is the mechanism
Face and nose
Unknown, independent of histamine
What is the severe end of outcomes from opiate muscle rigidity? Management
Which agents is it most common with
Difficulty in ventilating
Coadministration of induction agents and benzos
Muscle relaxants
Naloxone
Commonest with phenylpiperidines such as pethadine
Which opiates most markedly reduces shivering
Uses
Pethadine
Tramadol to a lesser extent
Maintaining hypothermia, managing shivering from epidurals, blood transfusions, postop.
Non opiate effects of pethadine
Local anaesthetic
Quinidine like antiarrhythmic effect
Effects of pethadine overdose
Cardiovascular collapse
Mydriasis
Hyperreflexia
Convulsions
Respiratory depression
What metabolite of morphine can causes long term issues? What issues?
Morphine 3 glucuronide
Neuroexictation, opioid antagonism causing hyperalgesia
Effect of norpethidine accumulation
Mood changes
Anxiety
Can have fatal effects
How protein bound are common opiates?
Alfentanil 92%
Fentanyl 85%
Remifentanil 70%
Naloxone 40%
Morphine 35%
Codeine 10%
Elimination half lives of common opioids
Remi 15mins
Naloxone 70mins
Alf and fent 100mins
Codeine and morphine 180mins
Tramadol 360mins
Vd of Alf, fent, codeine, morphine, Remi
L/kg
Alf 0.8
Fent 4
Codeien 5.4
Morphine 3.5
Remi 0.35
Timeframe of resp depression after intrathecal morphine
6-10hours
What side effects occur more often with intrathecal opiates
Nausea
Urinary retention
Puritis
What pharmacokinetic property of an opiate predicts it having a long effect intrathecally
Hydrophilic
Lipophilic bind rapidly to local sites then are absorbed intravascuarly
What features of opioids lead them to be absorbed into the csf from epdural administration
How much morphine crosses the dura
Lipophilicity
Molecular size
5%
In what time fram would epidural sufentanil, fentanyl and morphine peak in the csf
Suf - 6mins
fent - 20mins
Morphine 240 mins
Rough effect of first pass metabolism on oral opiate bioavailability
Where does it occur
50%
Liver and intestinal wall
What can alter peak plasma concentration of im or sc opiates
By how much
Five fold
Body temp
Site of admin
Haemodynamic status
What plasma proteins do opiates bind to
Mainly alpha1 acid glycoprotein but also albumin
Fent and Alf. Also bind to beta globulins
Morphine is mainly bound to albumin
What group of drugs would displace opiates from protiens increasing free fraction
Basic amines
Are opiates weak bases or acids
Main pKa range
Extreams
Bases
Most around 7.9 (morphine) to 8.4 (fent)
Extreams are Alf at 6.5 and tramadol at 9.4
Significance of Alfs pKa
PKa 6.5 thus mainly unionised thus lipid soluble
What occurs to opiates in an acidic CNS environment
Significance due to receptor interaction?
Ion trapping - unionised enters, becomes ionised then trapped,
Ionised form activates recpetor
Elimination of opiates
What is the primary determinant for clearance
Phase one and two metabolism. In liver with renal excretion of hydrophilic metabolites
Hepatic blood flow
Specific metabolism of morphine
Glucuronidation (mainly liver, some in kidney and gi tract):
60-80% bio transformation to M3G
10% to M6G
Rest sulphation (higher in neonates who struggle to glucuronidate)
90% excreteted in urine
Rest in bile sweat and breast milk
Significance of M6G
2-4 times more potent than morphine with longer half life.
Can cross bbb and is then eliminated even slower!
How is diamorphine activated, to what?
Are the metabolites hydrophilic or hydrophobic
Rapid deacetylation in the csf, liver and plasma to 6monoacetylmorphine and morphine
Hydrophilic
How is codeine metabolised
In liver to codeine conjugates and norcodeine with some urinary excretion of free codeine
10% metabolised to morphine by cyp2d6 (missing in 8% of Western Europeans)
Metabolism of pethadine
Hydrolysis to pethadinic acid and n-demethylation to norpethidine which is hydrolysed to norpethidinic acid
Causes enzyme induction increasing proportion converted to norpethidine with chronic use (or with other enzyme inducers)
Why does fent have a large volume of distribution
Impact on metabolism
Very lipid soluble
Rapid and continued peripheral tissue uptake limiting initial hepatic metabolism
May cause subsequent peaks as released and concentrations can vary 13 fold with perfusion
How is fentanyl metabolised
Hepatic to inactive metabolites which are excreted in the urine
How is remifentanyl metabolised with characteristics
Widespread and rapid non saturatable metabolism by desterification to carboxylic acid metabolite by non specific esterases in blood and tissues
Is the main metabolite of Remi active or inactive
How is it excreted
Active but not clinically significant
Excreted in urine but no worries even in renal failure as so weak
What causes offset of Remi - metabolism, redistribution or excretion
Metabolism
What is context sensitive half life
Half life in the context do duration of infusion
As infusion length increases more drug sequestered in fat so causes longer t1/2 as it returns to central compartment
What is the effect of a long infusion of Remi on t1/2
What about fentanyl
Remi - none
Fentanyl - increases from 3-5 phos to 7-12hrs
What weight should opiate dosing be based on?
When should obesity be a caution in opiates
Ideal body weight
Caution in long infusions except Remi as can cause very long context sensitive Half life
Which opiates are effected by renal failure? What happens
Morphine - huge increase in elimination half life of glucuronidated metabolites from 4 to up to 120hrs.
Pethadine - norpethidine accumulation, with CNS side effects not mediated by opioid receptors and thus not reversible with narcan
Effect of hepatic failure on opiates
Very little except in transplantation and fulment hepatic failure. Other organs eg kidneys and gi tract take bigger role.
Reduction in liver clearance will decrease first pass increasing bioavailability of oramorph
Some issues such as synergistic CNS depression from encephalopathy need to be considered.
Acidosis can cause ion trapping increasing effect
Drug drug interactions of opiates
Synergistic CNS depression with other CNS depressants eg propofol and benzos
MOAIs can cause fatal sequalae especially tramadol and pethadine - can be excitatory or inhibitory reactions
Which opiate is safest with moais
Morphine
Highest receptor affinity of naloxone
Mop
Duration of action of naloxone
30mins
What symptoms can naloxone help with
Resp depression
Itching
Urinary retention
Oral bioavailability of naloxone
2%
What is naltrexone
Analog of naloxone with a longer t1/2 of 8hrs
Effective orally due to low first pass metabolism
Blocks opiate euphoria so used in dependency management
HOw does tramadol act?
Weak agonist at all opioid receptors (with slight preferece to MOP)
Blocks NA and 5HT reuptake
Facilitates release of 5HT
Potency of tramadol at opiate receptors vs morphine
Roughly 10%
What are the isomers of tramadol
Significance
+ and - , comes as racemic mix
Have separate effects
+ for mop and 5Ht
- for na
Oral bioavailability of tramadol
Protein binding
68%
20%
Metabolism of tramadol
Hepatic
Demethylation and conjugation
Excretion of metabolites in urine
Metabolites very active so caution in renal failure
Side effects of tramadol
Less resp depression than equianalgesic dose of morphine
Minimal cvs effects
Dizziness
Sedation
Nausea
Dry mouth
Sweating
Rashes
Physical dependence
Pharmacokinetic properties of nsaids
Consequence
Rapid onset all routes
Highly protein bound
Small vol of distribution
Unbound fraction active
Effects potentiated by other protein bound drugs eg oral anticoagulants, hypoglycaemics, sulphonamides, anticonvulsants
Difference between aspirin and nsaid actions on cox
Aspirin acetalates irreversibly
NSAIDs act by competative inhibition
Main effect of nsaid cox inhibition
Decreased prostaglandin synthesis
What activates arachadronic acid
Phospholipase
Cox independent pathways from arachidonic acid
5 lipoxygenase to leukotrines
11,12,15 Lipoxygenase to hydroporoxhkosalenoic acid
Products of cox metabolism of arachidonic acid
Prostaglandins
Thromboxane a2
Prostacyclin
Functions of prostaglandins
Gastric protection
Maintainance of renal tubular function
Renal vasodilation
Bronchodilation
Vasodilation
Prevents platelet adhesion
Base group of prostaglandins
Eicosanoid (20 carbon chain) from aa
Where is cox 1 found
What does it do
Structure
ER of prostaglandin producing cells integrated into the lipid bilayer
Adds a 15 hydroperoxy group to aa forming pgg2 then reduces it to form pgh2 - has two active sites a cyclooxygenase site and a peroxidase site with a channel allowing aa access.
What makes cox 2 different to cox 1
Overall slightly lighter with a similar structure to cox 1 but larger volume central channel and slightly different aa structure allowing binding of larger drugs.
Where is cox 2 found? What stimulates its production? By how much?
Found in brain, kidneys, uterus, synovial cells, fibroblasts. Increases 10-80 fold when exposed to growth factor, cytokines, bacterial lipopolysaccarides
NNT for ibuprofen post op
Morphine?
Codeine
2.4
Morphine 2.9
Codeine 16.7!
How much do NSAIDs reduce opiate consumption
25-50%
Opiate side effects
Bleeding
Gastric ulcers
Bronchospasm
Renal impairment
What proportion of asthmatics have difficulties with NSAIDs
10-15%
How common is nsaid induced renal impairment post op
What raises risk
Rare,
Age, other nephrotoxics, vasoconstrictor use
Examples of cox 2 inhibitors
Celecoxib
Etorcoxib
Parecoxib
Meloxicam
What is the general problem with cox2 inhibitors
Why
Increased prothrombotic issues esp cardiovascular
Inhibition of endothelial prostacyclin which causes platelet disaggregation
NNT for parecoxib 40mg
2.2!
Advantages of cox 2 inhibitors
Less (not none) peptic ulceration
No impaired platelet function (no COX 2 in plateletls)
Effect of cox 2 on renal function
Similar to normal NSAIDs
What is parecoxib converted into after administration
Valdecoxib
What is the benefit of paracetamols lower protein binding vs NSAIDs
Less drug drug interactions
How does paracetamol work
Inhibits prostaglandin synthesis in the CNS - minimal effect peripherally
No clear binding site ? Central cox 2 or 3 but just hypothesis not proven
? Prostaglandin syntheisis inhibition at transcriptional level
. Cannaboid receptor agonist
NNT of paracetamol
What about combination with codeine
3.8
Combo 2.2 - much better than either alone
Who is more at risk of paracetamol related liver damage
Why
Those on enzyme inducers
Degradation of paracetamol to toxic NAPQI is CYP450 dependant, other routes are enzyme in dependant conjugation.
When is paracetamol toxicity damage at is maximum
What dose in 24o leads to significant damage
3-4 days after injestion
>150mg/kg
Examples of alpha 2 agonists
Clonidine
Dexmedetomidine
Side effects of alpha 2 agonists as an analgesic
Sedation
Hypotension
Bradycardia
Most effective way of administering clonidine
Epidural
Distribution half life of dexmedetomidine
Terminal half life
Vd
8 mins
3 hrs
170L
Mechanisms of anticonvulsants in neuropathic pain
Frequency dependant na channel block
Calcium channel blockade
Potentiation of gaba
NNT and NNH for carbamazepine
2.6
3.4
Side effects of anticonvulsants as analgesics
Sedations
Rash
Anorexia
Dizziness
Ataxia
Steven Johnson syndrome
Hepatic impairment
Renal failure
How does amitryptiline work as an analgesic
Inhibition of adrenaline reuptake enhancing decending inhibititory pain pathways
Side effects of tcas
Dry mouth
Sedation
Postural hypotension
Glaucoma
Paralytic ilius
Arrhythmia
What are the cannaboid receptors
Where are they found
GPCRs
CB1 brain and spinal cord
CB2 peripherally
Examples of cannaboid receptor agonists
Delta9 tetrahydrocannabinol (natural active component) - highly lipophilic but low potency
Nabilone - less lipophilic more potent
Anandamide - endogenous ligand CB1
Effects of delta 9 tetrahydrocannabinol
Antiemetic
Analgesia
Tachycardia
Hypotension
Weakness
Increased appetite
Euphoria then drowsiness
Psychological interference
What is the dose of a lidocaine analgesic 8ish fusion
0.5-1.5mg/kg/hr
NMDA receptor involvemtn in pain
Spinal central sensitisation pathways after damage
Types of pain ketamine effective against
Both Nociceptive and neuropathic
Time to peak effect of alfentanil?
Duration
90s
5-10mins
Potency of alfentanil vs morphine
10-20times
Contraindication to alfentanil, Remi and fentanyl
MOAI
Potency of codeine vs morphine
20%
Other potentially benfiecial effects of codeine beyond analgesia
Antidiarrhoeal
Antitussive
Bioavailability of diclofenac
60%
Doses of diclofenac by route
Oral 75-150mg/day in 2-3 divided doses
Rectal 100mg 18hourly (150mg/day)
IM 75mg Bd
iV 75mg 6hrly
Metabolism of diclofenac
Hepatic hydroxylation then conjugation followed by renal excretion
Potency of fentanyl vs morphine
60-80x
Cardiovascular effect of fentanyl
Minimal hence use in cardiac anaesthesia.
In very high doses some Bradycardia and hypotension
Paediatric dose of ibuprofen
20mg/kg in divided doses
Epidural fent and morphine dose
Much the same as iV (50-100mcg and 5-10mg)
Intrathecal morphine dose
0.2-1mg
Standard concentration of remifentanil for tci
50mcg/ml
How long is reconsitituted Remi stable for
24hrs at room temp
