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Pharmacology > Painkillers > Flashcards

Painkillers Flashcards

NSAIDs and Opioids

1
Q

Which enzyme liberates arachidonic acid from phospholipids?

A

Phospholipase A2.

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2
Q

Which pathway synthesises Leukotrienes?

A

Lipo-oxygenase Pathway

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3
Q

Which pathway forms the prostaglandins?

A

Cyclo-oxygenase (COX) pathway

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4
Q

Describe the distribution and inducibility of COX-1 and COX-2.

A

COX1: Typically active at all times in most tissues.
COX2: Inducible and tends to be present in inflamed tissues.

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5
Q

Name some important homeostatic functions of COX1.

A
  • GI Protection
  • Control of renal bloodflow (afferent arteriole)
  • Platelet aggregation.
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6
Q

Name some important homeostatic functions of COX2.

A
  • Tissue repair and healing.
  • Uterine contraction @ birth.
  • Inhibition of platelet aggregation.
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7
Q

Balance between what two prostaglandins can increase the risk of hypertension, MI and stroke?

A

TXA2 and PGI2.

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8
Q

What is the basic MOA of NSAIDs?

A

They compete with arachidonic acid for access to the active sites of the COX enzymes.

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9
Q

What are some of the local effects of NSAID’s?

A

Decrease inflamation (and thus pain) by decreasing the local production of prostaglandins. Examples include PGE2 and PGD2.

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10
Q

What is the main central effect of NSAID’s?

A

They decrease PGE2 synthesis in the dorsal horn, thereby decreasing neurotransmitter release and excitability in pain relay neurones.

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11
Q

How do NSAID’s have their anti-pyretic effects?

A

They inhibit COX2 in the hypothalamus which would be triggered to up prostaglandin synthesis by the arrival of cytokines (endogenous pyrogens).

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12
Q

Which NSAID is the ‘most’ COX1 specific?

A

Aspirin?

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13
Q

Which NSAID is the most COX ambiguous?

A

Ibuprofen

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14
Q

Which NSAID is the most COX2 specific?

A

Class = coxibs.

Example drugs include Celecoxib and Parecoxib.

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15
Q

What would the Vd of an NSAID be and why?

A

Relatively low as they - Aspirin especially - are highly protein bound.

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16
Q

Talk about the absorption of NSAIDS.

A

They are weak acids so are absorbed almost completely. They don’t typically undergo first pass metabolism.

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17
Q

Where are they metabolised?

A

Liver

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18
Q

Explain the metabolism of Aspirin.

A

At therapeutic doses, aspirin is metabolised by conjugation with glycine and glucuronic acid. This can be explained via 1st order kinetics. In overdose, this process is overwhelmed and metabolism follows 0 order kinetics.

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19
Q

What are some of the GI ADRs of NSAIDs?

A

Dyspepsia, nausea, peptic ulceration, bleeding and perforation.

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20
Q

Explain some of the mechanisms involved in this damage.

A
  • Direct damage to the hydrophobic nature of the mucus layer by the acidic nature of NSAIDs as they sit in the stomach.
  • Decreases mucosal bloodflow.
  • Decrease mucus and bicarbonate secretion, all while increasing acid secretion.
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21
Q

Which other factors add to risk of GI bleeding?

A
  • Concomitant H.pylori infection.
  • Anticoagulant use.
  • History of peptic ulceration.
  • Glucocorticoid use.
  • Smoking
  • Alcohol.
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22
Q

What impacts on kidney function can NSAIDs have?

A

They decrease GFR by causing constriction of the afferent arteriole. This decreases bloodflow to the kidney medulla.

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23
Q

In which existing disease states is NSAID use most risky?

A

People with underlying CKD. Also, people with compromised bloodflow such as congestive heart faliure and liver cirrhosis + ascites.

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24
Q

What are the sequlae of the problems NSAIDs can cause for the kidney?

A

Patients can retain salt and water as well as dropping renin secretion, allowing them to hold onto K+ potentially leading to hyperkalaemia.

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25
Q

What is the ADR profile of the coxibs like?

A

They decrease GI ADR’s but - if switched to after an issue with non selective drugs - will not solve the problem instantly. Renal ADR’s remain.

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26
Q

What impact could coxibs have on blood coagulability?

A

They don’t decrease TXA2 but do decrease levels of PGI2. This would nullify the protective effect PGI2 has.

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27
Q

How does the analgesic effect of the coxibs compare to that of Ibuprofen?

A

SOME evidence that they are less effective.

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28
Q

In what situation would switching to coxibs be a good idea?

A

In the case of severe OA or RA.

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29
Q

How can NSAIDs exacerbate HF?

A

They cause salt and water retention.

They bring about vasoconstriction as prostaglandins would typically have a vasodilatory role in antagonising ADH.

30
Q

What effect do NSAIDs have on the efficacy of anti-hypertensives?

A

Decrease efficacy.

31
Q

What is the link between NSAIDs and MI’s and what does NICE say about this.

A

They are proven to increase the likelihood of thrombotic events. This is only likely to be a problem in people with underlying risk factors however. Also this is a problem with chronic use. NICE recommend that those people with underlying pro-thrombotic risks are not treated with any NSAIDs but ASPIRIN. Many people are though.

32
Q

What DDIs can happen because of the protein binding of NSAIDs?

A

They can displace other highly protein bound drugs such as:

  • Warfarin (bleeding increased)
  • Sulphonylureas (hypoglycaemia)
  • Methotrexate (liver damage and leukopenia)
  • Some immunosuppressants.
33
Q

Above what age can Aspirin be used?

A

16 is general advice; 12 from some sources. Aspirin, particularly if used in children recovering from a viral illness or chickenpox, can cause Reye’s syndrome.
Reye’s syndrome is characterised by encephalopathy and liver failure.

34
Q

Reye’s Syndrome

A
  • Damage to mitochondria in hepatocytes. Cells die via ATP depletion.
  • Ammonia builds up in blood that causes damage to astrocytes in the brain causing the characteristic encephalopathy. Brain becomes oedematous.
35
Q

Stages of Reye’s encephalopathy.

A

1) Quiet, sleepy and vomiting.
2) Stupor, seizures and decorticate (flexor) response / positioning
3) Coma and decerebrate (extensor) response with loss of pupillary reflexes.
4) Loss of deep reflexes and death.

36
Q

Bloods in Reye’s syndrome?

A

Increased ammonia, transaminases and prothrombin time as liver dysfunction decreases.
Inability to manage blood sugars by converting to/from glycogen.

37
Q

Treatment of Reye’s syndrome?

A
  • Manage oedema (mannitol).
  • Supportive care.
  • Induced hyperventilation.
38
Q

What effects can NSAID’s have on a PDA?

A

Can help to close it.

39
Q

What can paracetamol be used for?

A

Not an NSAID. Can be used for mild/moderate analgesia. Also has anti-pyretic properties.

40
Q

What is the MOA of Paracetamol?

A

Not fully understood. Although it is not an NSAID it does seem to have some central only COX-2 selective inhibition action in the CNS.

41
Q

How is paracetamol metabolised?

A

It is conjugated with glucuronic acid in the liver.

42
Q

What is NAPQI?

A

It is a minor, but very reactive, paracetamol breakdown product which oxidises thiol groups on key metabolic enzymes if in excess. This is not a problem at normal doses as it is deactivated by conjugation with glutathione. At high doses (overdose) however glutathione is depleted and NAPQI can build up to toxic levels leading to irreversible HEPATOCELLULAR AND RENAL TUBULAR damage.

43
Q

At what point does liver damage peak after paracetamol overdose?

A

3-4 days.

44
Q

Which measure is a sensitive indicator of damage in paracetamol overdose?

A

Prothrombin Time.

45
Q

How does paracetamol overdose initially present?

A

In the first 24 hours we would see nausea, vomiting and abdominal pain. Between 24-48 hours we would see liver damage and RUQ pain.

46
Q

How can we manage paracetamol overdose?

A

If the patient presents to ED soon after taking it we can give activated charcoal. Low risk intervention so any help it could give us makes it worth it. If significant ingestion proceed straight to N-acetylcysteine (replenishes stocks of glutathione) or wait for 4 hours and measure level before plotting result on treatment graph. Follow ED proforma.

47
Q

Why give NAC instead of glutathione?

A

NAC will make it into the hepatocytes (where it is needed) after IV injection, glutathione would not.

48
Q

What is the difference between nociception and pain?

A

Nociception is the purely neural mechanism whereby painful stimuli are sensed and represented as APs by nociceptors and then these signals are transmitted to the brain. Pain is how these nociceptive stimuli are interpreted in the context of other sensations and people’s past expriences and present psychological state. Indeed, it is possible to feel pain without nociceptive input (e.g. phantom limb pain).

49
Q

Mechanism of nociception.

A

Nociceptor is stimulated and releases Substance P and Glutamate. This activates a 1st order neurone which synapses with a 2nd order neurone in the dorsal horn which then deccusates and ascends. These synapse onto the third order neurone in the thalamus and from there project to the post-central gyrus (somato-sensory cortex).

50
Q

What is the WHO Analgesic ladder?

A

A stepwise approach to pharmacologically managing pain. Step 1 = simple analgesia such as paracetamol and NSAID’s. Step 2 = adding a weak opioid. Step 3 = adding a strong opioid e.g. Morphine/Fentanyl. For different types of pain we can also try different things (e.g. anticonvulsants, SNRIs (Venlafaxine) and tricyclic antidepressants) for neuropathic pain. If all of these things don’t work we can experiment with different administration routes (e.g intrathecal opioids).

51
Q

Via which receptor do opioid drugs have their main therapeutic effects?

A

The mu opioid receptor.

52
Q

How well is morphine absorbed by the gut?

A

Gut absorption is erratic and there is significant first pass effects (oral bioavaliability of only 40%) so oral doses need to be doubled over parenteral doses. Morphine, once absorbed, distributes rapidly throughout all tissues in the body - including across the placenta if this applies.

53
Q

How is morphine metabolised?

A

It is metabolised in the liver via conjugation with glucuronic acid forming M6G and M3G. M3G crosses the BBB better than unmodified morphine and has convulsant properties. Morphine is renally excreted.

54
Q

What characterises a strong opiate?

A

They are full mu agonists (morphine, fentanyl etc). They cause analgesia and euphoria but are more effective at respiratory depression, emetogenesis and slowing down peristalsis leading to constipation.

55
Q

What effect do opiates have on a patient’s pupil?

A

They lead to miosis - pupillary constriction.

56
Q

Why may strong opiates be dangerous in asthmatics?

A

They can lead to mast cell degranulation and histamine release that may worsen a baseline tendency toward bronchoconstriction.

57
Q

How does fentanyl differ from morphine?

A

It is a parenteral only drug with a corresponding very high bioavaliability. It is highly lipophillic and protein bound and crosses the BBB readily. It is safer in renal impairment than morphine as it is deactivated by CYP3A4 first before being removed by the kidneys. Potency is 100x as great and it has higher receptor affinity.

58
Q

What makes codeine different to (weaker than) Morphine?

A

It is converted by the polymorphic CYP2D6 into Morphine and the expression of this is variable so its effect is also variable. Some drugs, such as Fluoxetine, inhibit this enzyme so less codeine is converted to morphine. Potency is about a tenth of that of Morphine.

59
Q

What special characteristic does Buprenorphine have?

A

It is a mixed agonist/antagonist. It can also be delivered sublingually, buccaly or via a transdermal patch. It is very safe in renal impairment as it is metabolised in Phase 1 via CYP3A4, then in Phase 2 undergoes glucoronidation before being excreted in bile.

60
Q

What characteristic of buprenorphine gives it its mixed agonist, antagonist properties.

A

It has an incredibly high affinity for the mu opioid receptor but a relatively low intrinsic efficacy. It is also an antagonist at the kappa receptors.

61
Q

How does the respiratory depression of buprenorphine compare to other opioids.
What effect does it have on BP?

A

It is less.

Can drop BP however.

62
Q

Outside of chronic pain, where can buprenorphine be used. Why does it work for this?

A

Treatment of opioid addiction. It blocks receptors so other opioids will not bind and give the pleasurable effects but has just enough intrinsic efficacy to stave off withdrawal symptoms.

63
Q

Give the name of the most commonly used opioid antagonist.

A

Naloxone.

64
Q

Describe the main problem with naloxone.

A

It rapidly distributes throughout the body (very lipophilic) and thus quickly displaces the opioid on which the person has overdosed. They wake up quickly and can be violent. But, its half life is shorter than the opioids it antagonises so if the person is not placed on an infusion they may well become resp depressed again.

65
Q

Is there an opioid against which Naloxone cannot be used?

A

Yes, buprenorphine has a higher affinity for the mu opioid receptor than Naloxone and it will not displace it. N.B. Big naloxone boluses can reverse this.

66
Q

After / instead of an initial bolus of Naloxone, is there a way of preventing the symptoms of opiate OD from returning?

A

Yes, give the person a long and slow naloxone infusion until the intoxicating agent has had time to leave their system.

67
Q

List some other common side effects of opiates not yet mentioned?

A
  • Withdrawal/dependence
  • Decreased sex drive.
  • Hypotension and bradycardia.
68
Q

Why should we avoid opiates in head injuries / raised ICP?

A

The conjugation product M3G can cross the BBB having an irritant/inflamatory/proconvulsant effect on the brain.

69
Q

In what way are opiates useful for terminal patients presenting with SoB?

A

They decrease CO2 induced drive to breath.

70
Q

If a patient is taking regular morphine twice daily and x doses of PRN morphine how do you recalculate their morphine requirement.

A

Sum up all of the morphine they have taken in a day (including PRN). Divide total morphine by 2 to get the new regular dose (e.g. twice daily) and divide this total morphine requirement by 6 to get the PRN dose.

71
Q

What special requirements must be fulfilled for an opiate (or any controlled drug prescription) to be valid.

A

-Full date, full address and full name for both prescriber and patient. The form of the drug (e.g. tablets/syrup/patches etc) should be written clearly, unit written clearly and the total amount of medicine you want to pharmacist to supply written in words and numbers. E.g. for Paracetamol you could write 56 tablets but for Morphine (where you must also specify the preparation) you must write ‘supply fifty-six (56) tablets’

Pharmacology (10 decks)

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