28. Non-steroidal Anti-Inflammatory Drugs Flashcards
How do NSAIDs exert their effects?
Non-steroidal anti-inflammatory drugs (NSAIDs)
exert their effects
by inhibiting the action of the
enzyme cyclo-oxygenase (COX)
and therefore reducing the production
of the inflammatory prostanoids,
These include thromboxane, prostacyclin and prostaglandin. The lack of prostaglandin causes most of the adverse effects of NSAIDs. as shown below:
Fig. 28.1 Pathway for prostaglandin and leukotriene synthesis
CELL PHOSPHOLIPID BILAYER
| | Phospholipase A2 | | \/ lipoxygenase ARACHIDONIC ACID --------------------> LEUKOTRIENES | | | COX | \/ PROSTANOIDS
Describe the distribution of cyclo-oxygenase.
There are two types of COX when
discussing NSAIDs:
COX 1 and COX 2.
> COX 1 (constitutive) is found in most cells.
> COX 2 (inducible) is undetectable in
most normal tissue but found in
abundance in macrophages
and other cells of inflammation.
• COX 2 catalyses the formation of inflammatory mediators and is therefore the
enzyme that needs to be inhibited
in order to decrease pain and inflammation.
In theory, if COX 2 could be inhibited without
affecting COX 1,
symptoms would be improved with minimal or no side effects. In practice, this is not the case as COX 2 inhibitors still show the side-effect profile of non-specific agents.
> COX 3 discovered in 2002,
it is an isoenzyme most likely to be a CNS
variant of COX 1.
It is the site of action of paracetamol.
What are the main actions of prostacyclin and thromboxane?
> Prostacyclin is a vasodilator and
prevents formation of platelet plug in
primary haemostasis.
> Thromboxane is produced by platelets.
It is a vasoconstrictor and a
potent platelet aggregator.
These prostanoids are in fine balance in health.
Describe the main actions of
prostaglandins.
Prostaglandins –
nine different receptors
result in varied actions, e.g.:
> PGE2 –
↓ gastric acid secretion,
↑ gastric mucous secretion
> PGI2 –
vasodilatation,
platelet aggregation
> PGF2α –
uterine contraction,
bronchoconstriction.
Classify the NSAIDs.
> NSAIDs may be classified according to their structure:
- Acetylsalicylic acids, e.g. aspirin
- Phenylacetic acids, e.g. diclofenac
- Carboacetic acids, e.g. indomethacin
- Propionic acids, e.g. ibuprofen
- Enolic acids, e.g. piroxicam
> NSAIDs may also be classified
according to their
inhibition of cyclo- oxygenase:
• Non-selective COX inhibitors,
e.g. aspirin, diclofenac, ibuprofen
• Selective COX 2 inhibitors,
e.g. parecoxib.
What are the indications for use of NSAIDs?
> NSAIDs are used therapeutically
for their anti-inflammatory
and analgesic effects.
In the management of acute pain,
NSAIDs have an opioid-sparing effect.
> Aspirin compared to the other NSAIDs has a unique anti-platelet action, which is used therapeutically in the prevention of arterial thrombosis (myocardial infarction and cerebrovascular accident).
What are the main
contraindications to the use
of NSAIDs?
> Relative contraindications to NSAIDs include renal impairment, history of gastrointestinal bleeding, heart failure, hypertension, coagulation defects.
> Absolute contraindications
include proven
hypersensitivity to aspirin or
any NSAIDs.
> Assess the hydration status of the
patient before prescribing NSAIDs.
There is a risk of precipitating renal failure
if NSAIDs are administered to
patients who are dehydrated.
> NSAIDs may enhance
the effects of warfarin.
> NSAIDs may worsen asthma in 10–20% of patients; they are contraindicated if aspirin or any other NSAIDs have precipitated attacks of asthma, although this occurs rarely in children.
> Aspirin should not be given to children under 12 years for analgesia or children under 15 years as an antipyretic because of the risk of Reye’s syndrome (aspirin-induced liver failure secondary to mitochondrial dysfunction).
What are the main side effects of NSAIDs?
The more an NSAID blocks
COX 1, the greater is its tendency to cause
peptic ulceration and promote bleeding.
Selective COX 2 inhibitors cause
less bleeding and fewer ulcers
than other NSAIDs
but certain drugs in this group have been associated with an increased incidence of thrombotic complications, especially myocardial infarction
(rofecoxib was withdrawn in
2004 because of an increased
incidence of myocardial infarction).
The following list summarises the
main side effects of NSAIDs:
1
NSAID-induced exacerbation of asthma (approximately 10–20% of asthmatics affected).
The mechanism is thought to involve increased
production of bronchoconstricting leukotrienes.
2
Gastrointestinal bleeding –
NSAIDs reduce circulating prostaglandins that
are essential in maintaining gastric mucosal integrity.
3 Acute kidney injury may be induced by NSAIDs in vulnerable patients, e.g. pre-existing renal dysfunction, diabetics, elderly or dehydrated patients.
The mechanism involves reduced
levels of prostacyclin,
which
are required to maintain renal perfusion.
> Platelet dysfunction –
related to reduced thromboxane production.
This is seen only with the non-specific COX inhibitors, not with the selective COX 2 inhibitors.
PARACETAMOL
NSAIDs
- Tablets: 500 mg
- Suppositories: 125/500 mg and 1 g
- Solution: 1 g in 100 mL
DOSE
- Adults: 1 g 6 hourly
- Children: first dose
15–30 mg/kg followed by
15 mg/kg 6 hourly
Max 90 mg/kg/24 hourly
MOA
• Central action via COX 3 inhibition
which is
associated with
↓ brain PGE2 levels?
ABSORPTION/ DISTRIBUTION • Absorbed in small bowel • Oral bioavailability 80% • Protein binding 10% • Modulates endogenous cannabinoid system
USES
• Analgesia
• Antipyretic
Paracetamol Effects
ME
METABOLISM
AND EXCRETION
• Hepatic metabolism mainly
to glucuronide and sulphate
metabolites (30%)
• Actively excreted in urine,
small amount unchanged
• 10% metabolised by P450
system to N-acetyl-p-amino
benzoquinoneimine
(NAPQI) = TOXIC
• Genetic polymorphism of
enzymes determines how
much NAPQI is produced
• In normal doses, NAPQI is rapidly conjugated by glutathione and its harmless products excreted in urine
• Once glutathione is
exhausted, NAPQI
accumulates causing
liver failure
• To treat OD – assess ABCD and make appropriate intervention. Give oral methionine (enhances glutathione synthesis)
and/or IV N-acetylcysteine (parvolex), which is hydrolysed to a precursor of glutathione
EFFECTS
CVS
• IV solution can
cause hypotension
and bradycardia if
given rapidly
CNS
• Analgesia
• Antipyretic
OTHER • Rash • Idiopathic thrombocytopenia • Analgesic nephropathy • Toxic in OD
CHEMICAL PROPERTIES
• Para-aminophenol
ASPIRIN
Prep
Dosing
MOA
ASPIRIN
Salicyclic acid derivative
NSAIDs
• Tablets: 75 and 300 mg
DOSE
• Angina and stroke prophylaxis: 75 mg od
• Post MI and thrombotic stroke
300 mg as one-off dose,
then continue with 75 mg od
• Analgesia: 300–900 mg
6 hourly 300 mg
• Max dose 4 g/24 hourly
MOA
• Irreversible COX 1
• Pro-drug inhibitor,
modifies action of COX 2
• ↑ Affinity for COX 1 at
low dose
• Selectively inhibits
production of TXA2
in platelets and =
inhibits aggregation
Aspirin
Chem Prop
AD
ME
CHEMICAL PROPERTIES
- Salicylate
- Weak acid, pKa 3.0
- Poorly ionised in acidic environment of stomach.
↑ pH & larger surface area of
small intestine cause aspirin
to be absorbed rapidly.
METABOLISM
AND EXCRETION
• Hepatic and intestinal metabolism by
ester hydrolysis to
salicyclic acid
(active metabolite)
• Further conjugated to salicyluric acid
(inactive metabolite)
• First-order kinetics in
low dose, becoming
zero order in overdose
• Excreted in urine
ABSORPTION/
DISTRIBUTION
• Absorbed mainly in small bowel
• 85%PPB
Aspirin
Uses
S/E
USES
• Analgesia
• Anti-inflammatory
• Anti-platelet in MI/CVA, etc. EFFECTS
RS
• 20% of asthmatics sensitive
to NSAIDs which
can cause bronchoconstriction
GI
• ↑ Risk of GI bleeding and ulceration because
inhibition of prostaglandin (PG) synthesis
causes ↓mucosal protection
• Hepatotoxic causing transaminitis
RENAL
• Inhibition of PGs and prostacyclin
causes local hypoxia
and ↓ renal perfusion
CVS • ↓ Endoperoxidases and thromboxane A2 =↓ platelet aggregation and ↓ vasoconstriction, = cardioprotective
• NB effects on platelet irreversible. New platelets must be synthesised to reverse effect
• Fluid retention can
precipitate heart failure
DRUG INTERACTIONS • Care with warfarin – NSAIDs are highly protein bound and so may displace warfarin
• May ↑ lithium levels
OTHER
• Toxic in overdose
• Reye’s syndrome in children
DICLOFENAC
EFFECTS
RS
• 20% of asthmatics
are
sensitive to NSAIDs
GI
• As for aspirin but
less GI upset
RENAL
• Inhibition of prostaglandins and prostacyclin's causes local hypoxia and ↓ renal perfusion
CVS
• Reversible inhibition of
platelet function, little
effect on bleeding time
OTHER
• Affects neutrophil function
• Renin and aldosterone
concentration reduced by
up to 70%
• Risk of thrombosis
DICLOFENAC
AD
ME
ABSORPTION/ DISTRIBUTION • Well absorbed by all routes • Significant first-pass metabolism
• Oral bioavailability 60%
• 99.5% PPB, mainly to albumin so may displace oral anticoagulants
• VD 0.12–0.17 L/kg
METABOLISM
AND EXCRETION
• Hepatic metabolism
• Excreted in bile
