Pharmacology 7: NSAIDs and Narcotic Analgesics

Question 1

What are most established NSAIDs derived from?

Answer 1

carboxylic acid

Question 2

main therapeutic effects of NSAIDs?

Answer 2

analgesia
anti-inflammation
anti-pyresis

Question 3

primary mode of action of NSAIDs?

Answer 3

competitive inhibition of COX which converts arachidonic acid= produced through cleavage of membrane phospholipids, to eicosanoids e.g. prostanoids- PGs, prostacyclins and thromboxanes.
inhibition occurs as sit within COX-1 and 2, so compete with arachidonic acid for binding

Question 4

blocking which enzyme seems responsible for most NSAID ADRs?

Answer 4

COX-1

Question 5

which enzyme is considered the site for NSAIDs exerting their therapeutic anti-inflammatory/analgesic effect?

Answer 5

COX-2= induced in inflammatory cells following activation by cytokines.

Question 6

how does aspirin differ from the other NSAIDs in terms of its action on COX?

Answer 6

aspirin irreversibly inhibits COX enzymes by acetylation= covalent, which allows it to inhibit platelet aggregation through inhibition of COX-1 which inhibits thromboxane A2 production.
other NSAIDs reversibly inhibit COX

Question 7

describe how NSAIDs exert an ANALGESIC effect

Answer 7

inhibit COX-2, reducing PG synthesis hence reducing the senstitisation of nociceptors to inflammtory mediators- both peripherally and centrrally.
reduces headache pain as inhibits cerebral vasodilation mediated by PGs
May also have secondary effect on PG facilitation of afferent pain signal in SC dorsal horn neurones- central sensitisation-inhinit PGE2 acting on secondary nociceptive neurones in dorsal horn which would increase perception of pain.

Question 8

what do NSAIDs primarily reduce with respect to their anti-inflammtory action?

Answer 8

erythema, swelling and pain response assoc. with swelling through inhibition of COX-2 and hence PG prod.

Question 9

how do NSAIDs exert their antipyresis function?

Answer 9

inhibition of PG-E2 production, which is produced by the hypothalamus following the release of endogenous pyrogen IL-1 from macrophages when triggered by bacterial endotoxins, (IL-1 possibly induces COX-2 to stimulate PGE2 production?). PG-E2 elevates set point on central ‘thermostat’ of hypothalamus via EP3 receptor - Gi type GPCR, so decrease cAMP and increase Ca2+ in neurones regulating temperature causing increased heat production and reduced heat loss

Question 10

what type of elimination kinetics does aspirin exhibit?

Answer 10

dose-dependent, so low doses= 1st order, t1/2 4hrs, whereas high dose= 0 order kinetics

Question 11

ADRs of NSAIDs due to COX-1 inhibition?

Answer 11

gastric ulcers- haemorrhage, perforation, as inhibition of PGE2 production via COX-1 which protects gastric mucosa by increasing mucosal blood flow and stimulating alkali and mucus production which protects the mucosa from gastric acid production by parietal cells. Also stimulates cytoprotective mucus secretion throughout GI tract.
nausea, diarrhoea, GI discomfort- dyspepsia
Renal ADRs in susceptible patients- reversible reduction in GFR as PGE2 and PGI2 inhibition
hypersensitivity reactions- rashes, asthmatic bronchospasm and allergic response
prolonged bleeding time

Question 12

which patients are at particular risk of GI and renal ADRs of NSAIDs?

Answer 12

neonates, elderly and patients with compromised Renal, Hepatic- increased risk of GI bleeding and fluid retention, and Cardiac function- NSAIDs may impair renal function- inhibit PG production which dilates renal afferent arteriole, or reduced blood volume

Question 13

ADRs of selective COX-2 inhibitors?

Answer 13

Diclofenac and the selective inhibitors of cyclo-oxygenase-2 (celecoxib, etoricoxib, and parecoxib) are contra-indicated in ischaemic heart disease, cerebrovascular disease, peripheral arterial disease, and mild to severe heart failure.
COX-2 selective inhibitors, diclofenac (150 mg daily) and ibuprofen (2.4 g daily) are associated with an increased risk of thrombotic events.
Selective inhibitors of COX-2 are associated with a lower risk of serious upper gastro-intestinal side-effects than non-selective NSAIDs
selective COX-2 assoc with increased risk of hypertension, cardiac and renal failure

Question 14

important DDIs of NSAIDs and aspirin with non-NSAID drugs

Answer 14

with corticosteroids: corticosteroids may increase incidence and/or severity of ulceration assoc. with NSAIDs, increasing possibility of GI bleeding
aspirin and warfarin- aspirin displaces warfarin for plasma protein binding sites as aspirin=class II drug, so warfarin= higher free plasma concentration, more at risk of toxic SEs= higher bleeding risk, AND both affect platelet aggregation= PDs
NSAIDs and ACEIs- NSAIDs can attenuate their action by blocking prod. of vasodilating PGs, so may massively reduced GFR
with sulfonylureas- increase risk of hypoglycameia
with methotrexate- increase risk of MTX ADRs

Question 15

what monitoring is required for patients on chronic NSAID therapy?

Answer 15

regular review of GI symptoms

monitor renal function

Question 16

why might aspirin be useful in GI cancer prophylaxis?

Answer 16

inhibits PGE2 production which is synthesised by cancers in colon, rectum and possibly upper GI, and this PGE2 promotes tumour growth
may also be prophylactic in breast cancer and other cancers.

Question 17

1st agent of choice for mild to moderate cases of pain or fever?

Answer 17

paracetemol

Question 18

how does paracetemol appear to have an analgesic and antipyretic property?

Answer 18

Currently unknown mechanism – weak COX-1 / COX-
2 inhibitor.Considered to primarily act in CNS possibly on a COX-3 isoform and one of its metabolites in CNS can combine with arachidonic acid to form a substrate that inhibits COX-1 and -2 activity.

Question 19

within what time period should a paracetemol OD be ideally treated and with what?

Answer 19

within 8 hours
IV N-acetylcysteine- but this can protect the liver if infused up, and possibly beyond, 24 hrs of paracetemol ingestion
oral methionine= both increase hepatic glutathione levels

Question 20

after what time period is a patient likely to die of liver failure following paracetemol OD?

Answer 20

after 48 hours

Question 21

what damaging conditions may occur secondarily to paracetemol OD?

Answer 21

renal tubular necrosis

hypoglycaemic coma

Question 22

what may be monitored in patients on LT paracetemol?

Answer 22

hepatic and renal function

Question 23

where are endogenous opioids found in body?

Answer 23

specific parts of CNS and PNS: limbic system, thalamus, SC, primary afferent peripheral terminals

Question 24

3 major groups of endogenous opioids?

Answer 24

enkephalins
endorphins e.g. beta-endorphin from POMC
dynorphins e.g. dynorphin

Question 25

how is the period of effective analgesia extended with morphine?

Answer 25

one of its metabolic products= morphine-6-glucuronide is at least pharmacologically equivalent to morphine with t1/2=4-5hrs slow release oral morphine preps used in chronic pain control

Question 26

what effect do opiates have that is responsible for resp depression?

Answer 26

mu receptor mediated action on CO2 sensitivity

Question 27

opioid ADRs?

Answer 27

resp depression- action on mu receptors in brainstem euphoria confusion miosis- constricted pupil psychosis dependance tolerance drowsiness- due to central effect on brain (sedatory effect?) coma nausea- mu receptors in brainstem vomiting-direct stimulatory effect on vomiting centre in brain so may need to also prescribe an anti-emetic constipation- espec. codeine- given orally hypotension

Question 28

what enzyme allows conversion of membrane phospholipids to arachidonic acid?

Answer 28

phospholipase A2

Question 29

why are most NSAID ADRs mediated by inhibiton of COX-1?

Answer 29

constitutive expression of COX-1, found in wide range of tissue types PG synthesis via this enzyme has major cytoprotective role= gastric mucosa, myocardium and renal parenchyma as ensures optimised local perfusion-reduces ischaemia

Question 30

how do PGs contribute to increased vascular permeability?

Answer 30

don't do so directly, but synergise actions of bradykinin and histamine

Question 31

typical dosing route for NSAIDs?

Answer 31

oral | but many topical applications for soft tissue injury

Question 32

key factor in pharmacokinetics of NSAIDs in terms of drug distribution?

Answer 32

mainy heavily bound to plasma proteins- 90-99% *importance with DDIs, if displace drugs from their protein binding sites then increase free plasma conc and so can increase risk of drug toxicity

Question 33

what can be given to patients to offset GI ADRs in the LT with NSAID therapy?

Answer 33

PPIs e.g. lansoprazole, omeprazole | misoprostol- synthetic PGE1 analogue

Question 34

why do ADRs commonly occur with combination NSAIDs?

Answer 34

patients self-medicating with NSAIDs e.g. ibuprofen, and then receiving prescribed NSAIDs, PD DDI

Question 35

examples of highly protein bound drugs affected by NSAIDs?

Answer 35

sulphonylureas e.g. gliclazide warfarin methotrexate

Question 36

what is aspirin rapidly hydrolysed to in plasma?

Answer 36

salicylate

Question 37

therapeutic doses of paracetemol?

Answer 37

up to 8 500mg tablets/day

Question 38

how do opioids act via gate theory to inhibit pain?

Answer 38

inhibit substance P release from nerve terminals in dorsal horn of SC required for activation of 2nd order afferents for pain transmission*

Question 39

when is liver damage maximal after paracetamol OD?

Answer 39

3-4 days after OD nausea and vomiting= only early features, and usually settle within 24 hrs persistence beyond this and onset of right subcostal pain and tenderness usually indicates hepatic necrosis development signs of hepatic necrosis= jaundice, right subcostal pain/tenderness

Question 40

when should oral activated charcoal be considered following acute paracetemol OD?

Answer 40

if paracetamol in excess of 150mg/kg thought to have been ingested within previous hr but can give if within 4 hrs, reduce uptake by 50-90%.

Question 41

how can patients at risk of liver damage and hence requiring N-acetylcysteine following paracetemol OD be identified?

Answer 41

Single measurement of plasma paracetemol conc related to time from ingestion if at least 4 hrs from time of ingestion, plotted on a paracetemol treatment graph. N-acetylcysteine given immediately in those whose plasma-paracetamol concentration falls on or above the treatment line on the paracetamol treatment graph. And in those who present 8–24 hours after taking an acute overdose of more than 150 mg/kg of paracetamol, even if the plasma-paracetamol concentration is not yet available; acetylcysteine can be discontinued if the plasma-paracetamol concentration is later reported to be below the treatment line on the paracetamol treatment graph, provided that the patient is asymptomatic and liver function tests, serum creatinine and INR are normal. The prognostic accuracy of a plasma-paracetamol concentration taken after 15 hours is uncertain, but a concentration on or above the treatment line on the paracetamol treatment graph should be regarded as carrying a serious risk of liver damage. 0-36hrs can start N-acetylcysteine, oral methionine if can't give NAC IV and OD within 10-12 hrs and patient not vomiting.

Question 42

why might prescribing a NSAID to a known asthmatic worsen their airway narrowing?

Answer 42

inhibtion of COX means increase in arachidonic acid so more metabolised via lipo-oxygenase pathway which results in increased leukotriene production which contributes to airway inflammation in asthma.

Question 43

why is COX-1 constitutively expressed?

Answer 43

constant synthesis is required of PGs as very short t1/2= 10 mins

Question 44

what characteristic of COX-2 selective inhibitor's structure was designed in order to cause COX-2 selectivity?

Answer 44

large molecular structure so unable to sit in relatively narrow AS of COX-1 only approved for use in US and EU in short term treatment.

Question 45

via which bonds are NSAIDs bound to plasma proteins?

Answer 45

ionic bonds so drug once bound to plasma protein can be displaced from protein by other drugs *important for DDIs- NSAIDs may displace sulphonylureas, warfarin and methotrexate from plasma proteins, increasing their risk of ADRs

Question 46

what may influence your decision as to which NSAID to prescribe?

Answer 46

how severe is the pain? some more potent than others e.g. naproxen= highly potent BUT increased risk of ADRS e.g. skin rash, so may also want to ascertain other RFs in pateint for ADRs e.g. elderly- may be compromised renal function, so would want to prescribe an NSAID with less risk of ADRs. Cost? chronic pain= would use NSAID with a longer t1/2, do taking drug once daily, t1/2>10hrs dosing regimen to fit in with everyday activities e.g. naproxen= longer t1/2 so given less frequently. dominant disease state and individual patient response? elderly, previous GI ulcers, also on anti-platelet or corticosteroid therapy?- increased risk of GI ADRs to may prescribe selective COX-2 inhibitor.

Question 47

aspirin dose given daily for cardioprotective purpose?

Answer 47

75mg

Question 48

describe how peripheral sensitisation is mediated by PGs

Answer 48

PGE2 in particular following tissue injury binds to EP1 GPCR on C pain fibres. =GqGPCR= PLC- PIP2 to IP3 and DAG= increase Ca2+ sp increase NT release. Also increase neurona sensitivity to bradykinin, increase Na+ channel sensitivity and inhibit K+ channels. So increase C fibre activity. Increased sensitivity responsible for hyperalgesia= increased pain at normal threshold, and allodynia**NS**- activation of surrounding fibres? upregulation of NMDA receptors- increased excitation?

Question 49

how do PGs mediate central sensitisation causing pain?

Answer 49

increased cytokines in dorsal horn as increased nociceptive signalling peripherally. PGE2 binds to GPCR=Gs in dorsal horn- activates adenylyl cyclase, increase cAMP, activate PKA-phosphorylation of glycine receptor- reduce binding affinity so glycine can't bind to inhibit pain= increases sensitivity and discharge rate of secondary interneurones.

Question 50

therapuetic pharmacodynamic interactions of NSAIDs?

Answer 50

low-dose opiates= extends therapeutic range for treating pain so more pain can be treated, and reduces ADRs seen with opiates alone.

Question 51

DDIs with NSAIDs in combination?

Answer 51

- increase risk of ADRs, often occurs due to self medication with NSAIDs- PDs and PKs altered, PKs-disaplacement from plasma protein binding sites. - NSAIDs and low dose aspirin- compete for COX-1 so may interfere with cardiprotective function of aspirin.

Question 52

T1/2 of aspirin?

Answer 52

<30 mins, rapidly hydrolysed in plasma to salicylate

Question 53

T1/2 of salicylate at low doses of aspirin?

Answer 53

4hrs

Question 54

t1/2 of paracetemol given at therapeutic dose?

Answer 54

2-4hrs

Question 55

how is paracetemol normally metabolised at therapeutic doses?

Answer 55

1st order Pks mainly undergoes phase II metabolism with glucuronide (60%), 30% with sulphate 10% undergoes phase I oxidation producing toxic metabolite NAPQI= very reactive, free radical. This then detoxified with glutathione in phase II conjugation=linear, but limited by glutathione availability.

Question 56

ADR associated with IV paracetemol, and dose of paracetemol given by IV infusion?

Answer 56

hypotension >50kg= 1000 mg every 4-6hrs, max= 4000mg daily if 10-50kg= 15mg/kg every 4-6hrs, max= 60mg/kg daily.

Question 57

how does toxicity occur with paracetemol OD?

Answer 57

single doses >10g (>20 tablets) potentially fatal. PKs become zero order as phase II metabolism becomes saturated. So rather than 10% undergoing phase I oxidation, now most is undergoing this pathway, so increased toxic NAPQI produced. As phase II pathways saturated, glutathione conjugation pathway also saturated as rate limited, glutathione rapidly consumed and unavailable to remove NAPQI so more around to exert toxic effect, binding to sulfydryl groups on heaptocytes and mitochondria and promoting heaptocyte necrosis. Glutathione consumption also makes hepatocytes susceptible to damage from other free radicals which would glutathione would normally protect cells against. Can also cause renal failure.

Question 58

precursors of endogenous opioid peptides?

Answer 58

pro-enkephalin POMC pro-dynorphin

Question 59

why might giving opioids LT result in immunosuppression?

Answer 59

mu-opioid receptors expressed on lymphocytes so function inhibited

Question 60

which opioid receptor is involved most with giving pain relief (analgesia)?

Answer 60

mu receptor has important effects in brain (supraspinal) found pre and post synaptically

Question 61

where are kappa and delta opioid receptors found in the body?

Answer 61

``` kappa= SC- analgesia delta= widely distributed, acted on by enkephalins ```

Question 62

what happens when mu receptors activated?

Answer 62

increased permeability to K+, so hyperpolarisation and hence reduced neuronal excitability

Question 63

what happens when kappa receptors activated?

Answer 63

reduce Ca2+ influx via channels

Question 64

what happens when delta receptors activated?

Answer 64

reduce cAMP synthesis

Question 65

what can all subtypes of opioid receptor when activated definitely achieve in terms of activating a GPCR?

Answer 65

decrease cAMP

Question 66

In the pre-synaptic neurone (e.g. interneurone of substantia gelatinosa?) how can activation of the different subtypes of opioid receptor cause inhibition of pain?

Answer 66

ALL cause decrease in Ca2+ so vesicle containing substance P neurotransmitter is inhibited from fusing with the pre-synaptic membrane which is necessary for NT release and subsequent activation of 2nd order afferent to allow pain transmission. mu receptor activated- increase K+ efflux which will decrease IC Ca2+ kappa activated- inhibit Ca2+ channels so decrease Ca2+ delta activated- inhibition of adenylate cyclase, so decrease cAMP which decreases Ca2+

Question 67

via which receptor do most ADRs of opioids come about?

Answer 67

mu-opioid

Question 68

why is ADR of dependence with opioid drugs so problematic in terms of health risk to patient?

Answer 68

have to take the drug or will suffer severe withdrawal symptoms, but opioids also cause tolerance, so the dose of the drug will need to be increased to achieve the same desired therapeutic effect, and this will increase the risk of fatal respiratory depression, which often causes death.

Question 69

ADRs associated with kapa receptora?

Answer 69

dysphoria- low mood, distress e.g. with pentazocine

Question 70

how do agonist/antagonist properties of opioid drugs differ?

Answer 70

pure agonist= morphine partial agonsit= buprenorphine- unable to achieve maximal response even when all available receptors bound, but if more receptors were available, it may be able to achieve max effect and so become a full agonist. With a higher affinity but lower efficacy, it is more likely to bind to receptors than herorin, but less able to activate them so reduce rosk of ADRs? agonist/antagonist- action different depending on which opioid receptor it acts on, e.g. nalbuphine- antagonsit at mu, partial agonist at kappa, and weak agonist at delta. anatagonist= naloxone, important if patient overdoses on morphine and goes into resp depression, can reverse this.

Question 71

why does morphine have a LOW oral bioavailability?

Answer 71

poorly lipid-soluble= passive factor affecting absorption- poor, so not much of the drug reaches the systemic circulation in an unchanged form to exert its desired therapeutic effect.

Question 72

t1/2 of morphine?

Answer 72

1.3-6.7 hours

Question 73

t1/2 of methadone?

Answer 73

15-30 hours can be given as an oral syrup can maintain people dependent on opioids with this 90% oral bioavailability

Question 74

oral bioavailability of codeine?

Answer 74

90%

Question 75

t1/2 of herorin (diamorphine)?

Answer 75

5 mins

Question 76

why diamorphine such short t1/2?

Answer 76

ester bonds- rapidly broken down by esterases in blood and tissues, producing mono-acetyl morphine then MORPHINE= active drug.

Question 77

what is benefit of IV diamorphine?

Answer 77

acetyl groups make it very lipid soluble so IV allows easy access to brain by crossing BB barrier where then converted to morphine and so has an immediate euphoric effect. Morphine alone wouldn't pass as easily across BB barrier as not very lipid soluble due to presence of OH groups.

Question 78

codeine is a prod-drug. How is it activated?

Answer 78

via CYP450 system in liver- CYP2D6- degree of polymorphism so codeine may be ineffective in some people as lack this enzyme system, espec. in chinese patients. Converted to morphine.

Question 79

examples of opioids being used as anaesthetics?

Answer 79

Fentanyl- 100X more potent than morphine Alfentanil Remifentanil- short t1/2- hydrolysed very quickly. BUT can cause quite severe itching as cause cross linking of mast cells which cause histamine release.

Question 80

what might the opioid pethidine be used for?

Answer 80

analgesic in labour IM BUT prolongs labour and crosses placenta so naloxone has to be given to baby once born. Also musn't give frequent repeat doses as metabolite norpethidine can accumulate and cause convulsions.

Question 81

naloxone t1/2?

Answer 81

1-1.5hrs *morphine t1/2=4hrs, so effects of nalxone will wear off more quickly than morphine, so may need to give repeated doses, so must monitor patient. reverse resp depression with opioid toxicity. can also treat dependence- but causes withdrawal so very severe, done under very controlled conditions. can also give naltrexone=oral=t1/2 4hrs

Question 82

examples of schedule 2 controlled drugs-opioids?

Answer 82

morphine diamorphine pethidine remifentanil

Question 83

example of schedule 5 controlled drug-opioids?

Answer 83

codeine- can be sold OTC but pharmacists should keep invoices for any codeine sold as abuse potential.

Question 84

new endogenous opioid peptides and receptor?

Answer 84

ORL-1= opioid receptor like 1 nociceptin= peptide for this receptor. Then nocistatin- blocks nociceptin. also endomorphins 1 and 2= high affinity and specificity for mu receptor= possible future target to mimic these endomorphins.

Question 85

potential problems for patient when using opioids for day-surgery cases e.g. for optimal control of perioperative and postoperative pain?

Answer 85

nausea and sedation

Question 86

why would a patient on morphine for pain who is being switched to codeine be tapered off the morphine gradually?

Answer 86

prevent opioid withdrawal symptoms e.g. irritability, sweats, nausea, vomiting, diarrhoea, abdominal cramping, muscle pains, low energy, insomnia.

Question 87

why is aspirin not given to children?

Answer 87

fear of Reye's syndrome= hepatic encephalopathy and liver steatosis in young children.

Question 88

how is visceral pain normally treated?

Answer 88

with opioid analgesics

Question 89

why can fentanyl be useful for pain relief in a patient that suffers with intractable nausea or vomiting when taking opioids?

Answer 89

fentanyl can be given transdermally in those with chronic stabilised pain, and so ADRs of oral opioids avoided

Question 90

what is the main way in which tramadol has an analgesic action?

Answer 90

enhanced serotoninergic neurotransmission *serotoninergic neurones travel from the brainstem to the substantia gelatinosa, stimulating the inhibitory interneurones which release enkephalins which act on opioid receptors, inhibiting the ascending pain pathway.

Question 91

typical agent used in treating trigeminal neuralgia e.g. due to nerve compression or MS?

Answer 91

carbamazepine *CYP450 inducer gabapentin =anti-epileptics

Question 92

how do PGs cause local vasodilation/erythema?

Answer 92

PGE2 acts on Gs GPCRs- activates adenylate cyclase, increases cAMP, activates PKA= inhibits MLCK which normally phosphorylates myosin light chains, so light chain affinity for Ca2+ is reduced in arteriolar smooth muscle, causing relaxation hence vasodilation.