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Pharmacology. > 14. Analgesia > Flashcards

14. Analgesia Flashcards

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1
Q

How does clonidine work?

A

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

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2
Q

What kind of drug is paracetamol?

How does it work?

A

Atypical nsaid

Inhibits cox 1 and 2 and therefore prostaglandin synthesis
Increased cannabinoid receptor activation
Inhibits descending serotenergic pathways

Analgesic and antipyretic

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3
Q

What can paracetamol be useful for pre-op?

A

Given 1h prior to op, can stop central sensitisation

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4
Q

What is the onset time, peak and duration of paracetamol IV and oral?

A

IV = 5min, peak in 40-60 and lasts 6h

Oral = onset 40m, peak 1-2h

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5
Q

How is paracetamol excreted?

A

Renal

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6
Q

What are the toxic doses of paracetamol OD?

What is the treatment?
S/E?

A

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

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7
Q

What is the mechanism of aspirin?

A

Irreversible non-selective cox inhibitor.

Inhibits prostaglandin production, prostacyclins and thromboxane

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8
Q

What is the pathway of prostaglandin synthesis?

What drugs interact with the different steps?

What are the final products?

A

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

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9
Q

What do NSAIDs cause bronchospasm?

How many people does this effect?

A

Preventing formation of prostaglandin H2 causes arachidonic acid to go down other pathway to make leukotrienes

Effects 10-20%

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10
Q

What are the selective and non selective NSAIDs?

A

Non = aspirin, diclofenac, ketorolac and ibuprofen

Selective = parecoxib

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11
Q

What are the good and bad effects of aspirin?

A

Analgesia
N&V (stimulates CTZ)
Respiratory alkalosis
Metabolic acidosis
Blood sugar reduced at low doses and increased at high doses

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12
Q

What is the metabolism and excretion of aspirin?

A

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

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13
Q

What are the toxic levels of aspirin?

The effects?

The treatment?

A

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

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14
Q

What are the cox’s and where is each found/do?

A

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.

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15
Q

Do we usually use selective cox 2 inhibitors?

A

No most have been withdrawn due to higher risk of VTE

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16
Q

What are the different routes for NSAIDs and what drugs use each?

A

IV = ketorolac and parecoxib
Diclofenac: oral, IV or PR
Rest oral

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17
Q

What are the general kinetic features of NSAIDs and interactions?

A

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

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18
Q

When are NSAIDs used with caution?

A

Pre-eclampsia
Pregnancy
Surgeries with high bleeding or bleeding risk
Co-morbidities
No aspirin in kids (Reyes)

No increased risk with regional

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19
Q

What is opium?

A

Mix of alkaloids from papaver sominferum opium poppy juice

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20
Q

What are the difference between opiates and opioids?

A

Opiates are naturally occurring
Opioids are natural or synthetic with morphine like properties

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21
Q

What is a narcotic?

A

Narco is Greek for numb
Drugs with analgesic and sedative properties

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22
Q

Where are endogenous opioids mostly found?

A

Hypothalamus, pituitary, periductal aqua grey, brain stem and substantial gelatinosa

Also some peripheral

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23
Q

What are the three main categories of endogenous opiates?

Receptors?

Effects?

A

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

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24
Q

What type of receptors are opiate receptors and what are the three main types?

A

All GCPR

Mu, delta and kappa

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25
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)
26
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
27
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
28
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
29
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.
30
What are the different classification types for opiates?
Source Receptor affinity Potency Family
31
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.
32
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
33
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
34
What are the CVS effects of opioids?
Brady and hypotension due to decreased sympathetic tone Anaphylaxis and peripheral vasodilation due to histamine release
35
What are the neuroendocrine effects of opioids?
Reduced ACTH, prolactin and gnrh secretion Increased ADH
36
What are the urinary effects of opioids?
Retention due to increased detector tone and inhibition of voiding reflex
37
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.
38
What are the 4 different forms of u agonist and drugs?
Morphinans: morphine, codeine etc. Phenylpiperdines: pethidine, fentanyl and alfentanil Diphenolpropylamines: methadone Esters: remi
39
How did morphine get its name?
Morpheus the Greek god of dreams
40
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
41
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
42
What is papervertum?
Semi synthetic mix of 80% morphine, codeine and papeverine
43
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)
44
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
45
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
46
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.
47
How is fentanyl metabolised?
Dealkylated to norfentanyl - inactive
48
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
49
What ways can we give fentanyl?
Iv Patch (2 days to steady state) Lollipop (avoids first pass metabolism)
50
What is remi derived from and how does its speed and potency compare to fentanyl?
Fentanyl derivative Similar speed and potency
51
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.
52
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
53
What are the OD effects of tramadol?
Some Opiate signs e.g. small pupils Mostly serotonergic and can cause serotonin syndrome
54
What is the metabolism and excretion of tramadol?
Four different pathways and one having a greater u affinity than parent Can accumulate in AKI
55
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
56
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.
57
What is DHC? BA? Metabolism?
Synthetic codeine derivative 20% oral BA (poor absorption and high first pass) Metabolised to dihydromorphine and norhydrocone
58
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.
59
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
60
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
61
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

Pharmacology. (22 decks)

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