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Clinical Pharmacology > 9.1 NSAIDS > Flashcards

9.1 NSAIDS Flashcards

1
Q

how is arachidonic acid synthesised?

A

in diet, eat linoleic acid (vegetable oil), from this get arachidonic acid which is incorporated into phosphoplipids

phospholipase A2 will convert it back to arachidonic acid from phospholipids.

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2
Q

what can arachidonic acid be used in the synthesis of?

A

leukotrienes in the eicosanoid synthesis pathway

can use leukotriene receptor antagnoist medication against them e.g in asthma

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3
Q

what are the structural differences of COX1 and COX2?

A

cox2 has a larger and more flexible substrate channel than cox1, and a larger space where inhibitors bind

= can use different medications on them

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4
Q

what are the functions of COX1?

A

COX1

  • GI protection
  • platelet aggregation
  • vascular resistance
  • renal blood flow
  • chronic inflammation
  • chronic pain
  • raised blood pressure
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5
Q

what are the functions of COX2?

A

COX 2

  • renal homeostasis
  • tissue repair and healing
  • reproduction (uterine contractions)
  • inhibit platelet aggregation
  • chronic inflammation
  • chronic pain
  • fever
  • blood vessel permeability
  • tumour cell growth
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6
Q

Name 5 prostanoids (type of prostaglandins)

A

PGE2
PGF2A
PGD2

(play a role in pyrexia, pain and inflammation)

PGI2 - prostacyclin
TXA2 - thromboxane

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7
Q

what is the action of prostacyclin compared to thromboxane?

A

Prostacyclin is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator.

thromboxane however stimulates platelet aggregation and arterial constriction= opposing effects

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8
Q

what enhances the action of prostanoids?

A

local autocoids e.g bradykinin and histamine

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9
Q

what are COX 1 and COX 2 enzymes in the synthesis of?

A

in the synthesis of the prostanoids

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10
Q

what is the mode of action of nonsteroidal anti-inflammatory drugs (NSAIDS)?

A

inhibit COX enzymes and so get subsequent reduction in prostanoid synthesis
they compete with arachidonic acid for hydrophobic site of COX

used for their analgesic and anti-inflammatory effects

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11
Q

why is low dose aspirin not considered to be an NSAIDs?

A

low dose is an irreversible cox inhibitor

moderate is relegated to use as antiplatelet

high dose to see anti-inflammatory effects as it isnt as effective at lower dosages.

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12
Q

how do NSAIDS have analgesic effects?

A

local peripheral action at site of pain - greater efficacy if inflamed

central component associated with decreased PGE synthesis in dorsal horn = less neurotransmitter released = decreased excitability of neurones in pain relay after first dose but full analgesia after several days of dosing

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13
Q

how do NSAIDS have an anti-inflammatory effect?

A

reduction in prostaglandin production during injury esp. PGE and PGD2

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14
Q

how do NSAIDS have anti pyretic effects?

A

inhibit hypothalamic COX-2 where cytokine induced prostaglandin synthesis elevated

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15
Q

how do NSAIDs differentiate?

A

as to whether they’re more selective of COX1 or COX2

COX2 selective compounds inhibit COX2 with much greater selectivity than COX1 at therapeutic doses

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16
Q

what drugs are more COX1 selective than COX2?

A 
COX 1
asprin
iboprofen
naproxen
diclofenac
(non selective)
COX2
celecoxib
parencoxib
eteoricoxib
(selective)

THE -IBS

17
Q

Are NSAIDS acidic YES OR NO

A

yeah they’re weak acids especially COX1 inhibitors

18
Q

how are NSAIDS absorbed and metabolised?

A

absorbed in GI tract, some in stomach

usually don’t undergo first past elimination
highly protein bound with small Vd

hepatic metabolism to inactive products

19
Q

how is aspirin metabolised?

A

asprin -> salicyclic acid -> conjugated with glycine

saturated at high doses - 1st orer-> 0 order (overdose)

20
Q

what are the GI ADRs of NSAIDs?

A 
dyspepsia
nausea
peptic ulceration 
bleeding 
perforation
makes IBD worse
irritation and bleeding from rectal admin

this is because

  • less mucus and HCO3 secreted = more acid
  • decreased mucous blood flow = enhanced cytotoxicity and hypoxia
  • decreased hydrophobicity of mucus layer due to NSAIDS local action
21
Q

what puts you at risk of the GI ADRs of NSAIDS?

A 
age
prolonged use 
glucocorticoid sterioids (act in a similar way)
anticoagulants
smoking 
alcohol 
history of peptic ulceration
Helicobacter pylori
22
Q

what are the renal ADRs of use of NSAIDS?

A

get reversible

  • decreased GFR
  • increased creatinine
  • decrease renal medullary blood flow

more likely in underlying CKD and blood flow compromise

  • congestive heart failure
  • cirrhosis with ascites

otherwise

  • increased salt and water retention = hypertension and oedema
  • lower renin secretion ->hyperkalaemia
23
Q

how do ADRs vary between cox1 and cox2 inhibitors?

A

less GI ADRs, renal ADRs similar to COX1 agents, impair PGI2 potentially leading to unopposed aggregatory effects

24
Q

what are the cardiovascular ADRs of NSAIDS?

A

increased salt and water retention = exacerbate heart failure and increase BP

vasoconstriction through reduced ADH secretion by prostaglandins

increased risk of acute MI

25
Q

what are some DDI of NSAIDs?

A

NSAIDs and low dose asprin = compete for cox1 = decreased CVS protection

may interact with drugs that rely on protein binding as that is the mechanism of NSAIDs

e. g Sulfonylurea - hypoglycaemia
e. g methotrexate - accumulation and hepatoxicity in RA
e. g warfarin - increased risk of bleeding

26
Q

why should aspirin not be given to children under 12?

A

Reye’s syndrome

rapid progressive encephalopathy - febrile viral infections, not for children under 12

27
Q

how does paracetamol have analgesic effects?

A

COX2 selective inhibition in CNS (spinal cord) = decreased pain signals to higher centres

28
Q

what is NAPQI?

A

a minor oxidation product of paracetamol - highly reactive

normal doses, conjugation with glutathione renders it harmless

hepatic glutathione is limited - balance of conjugation determines build up of NAPQI

29
Q

what happens in a paracetamol overdose?

A

FIRST 24 HRS
nausea
vomiting
abdominal pain

24-48 HRS
liver damage
upper quadrant pain

3-4 DAYS
maximal liver damage

30
Q

what do you treat paracetamol overdose with?

A

acetylcysteine - a thiol donor for phase 2 metabolism

can get into hepatocytes easier than glutathione itself

Clinical Pharmacology (27 decks)

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