NSAIDS

Question 1

Outline the Gate Control Theory of pain, referring to the specific components which make it up.

Answer 1

The GCT theorises that pain is a two way regulation process between the peripheral nervous system (which detects tissue injury) and the brain (which can inhibit pain signals through defending inhibition). This is thought to occur in the dorsal horn of the spinal cord, specifically in lamina II, the substantia gelatinosa (SG).

The primary afferent nociceptor detects noxious stimuli and synapses with second order ascending spinothalamic tract, using the neurotransmitter ‘substance P’. This transmission can by inhibited through the inhibitory action of the interneurones of the SG. The SG can be induced by peripheral mechanoreceptors (i.e. ‘Rubbing it better’) and descending tracts from the nucleus raphe magnus (originating in the periaqueductal grey of the midbrain. It is inhibited by the primary afferent nociceptor.

Question 2

Describe the synthesis and role of prostanoids.

Answer 2

Prostanoids are a group of compounds derived from arachanoic acid, generated through the action of the cycloxygenase enzyme isoforms 1 and 2. Examples of prostanoids include prostacyclins, prostaglandins and thromboxane. Functions include regulation of vasodilation, platelet activity, immunomodulation, fever and hyperalgesia.

Question 3

Explain in general terms how NSAIDS work.

Answer 3

NSAIDS function by competitively inhibiting the COX-1/2 enzymes, which are involved in the synthesis of prostaglandins in tissues. Prostaglandins have a range of functions depending on the location of expression. Such functions include hyperalgesia, fever, vasodilation and immunomodulation. Inhibition of COX-2 removes these signs of inflammation, producing the desirable effect of NSAIDs.

Inhibition of the COX-1 enzyme, which is constitutive expressed in a range of tissues in the body, produces the adverse drug reactions seen in longer term NSAID use.

Question 4

Describe the difference in tissue expression, and function, of COX-1 and COX-2.

Answer 4

COX-1 is constitutively expressed in a range of tissues, including the heart, stomach and kidneys. Its function is to generate prostaglandins which maintain integrity and function of the organ, i.e cytoprotective.

The expression of COX-2 is indictable in the presence of inflammation. Inflammatory mediators which induce expression include bradykinin. Its activity in the presence of tissue damage result in the production of prostaglandins which mediate inflammation - i.e. Vasodilation, immunomodulation and hyperalgesia. Centrally, COX-2 may be involved in the generation of a fever through IL-1 signalling in the hypothalamus.

Question 5

What can be co-prescribed with an NSAID to minimise side effects?

Answer 5

A PPI can be prescribed with an NSAID in order to reduce gastric acid secretion and so minimise the risk of gastritis.

Question 6

Why should NSAIDS only be prescribed for the shortest amount of time possible?

Answer 6

Long term NSAID use increases the risk of serious side effects such as gastritis and peptic ulceration. A PPI can be co-prescribed to minimise the risk of this happening.

Question 7

What is the role of COX-1 in the body?

Answer 7

COX-1 is one form of the COX isozyme which functions to generate prostaglandins which have a cytoprotective function. They have effects such as maintaining blood supply to the heart, kidney and gastric mucosa, where they also reduce acid secretion and maintain alkaline mucus production. COX-1 is constitutively expressed throughout issues of the body.

Question 8

What is the role of COX-2 in the body?

Answer 8

COX-2 expression is induced in the presence of inflammation by local mediators such as bradykinin. It generates prostanoids such as prostaglandin which cause hyperalgesia, vasodilation, immunomodulation and fever (centrally)

Question 9

What are some of the common side effects of NSAIDS

Answer 9

NSAID side-effects are attributed to the non-selective inhibition of COX-1. Inhibition of this isozyme results in increased gastric mucosa permeability, reduced blood flow and reduced alkaline mucus secretion. This increases the risk of gastritis and peptic ulceration. To minimise the risk, a PPI can be given with NSAIDs.

NSAIDs can also reduce GFR.

NSAIDS can also induce hypersensitivity, resulting in a rash and/or bronchial asthma.

Prolong bleeding time due to reduction in thromboxane synthesis.

Question 10

What drug-drug interactions are important to consider when prescribing NSAIDs.

Answer 10

NSAIDs have a high protein binding fraction. Because of this they have the potential to displace other drugs which also bind plasma protein. These include methotrexate, warfarin and sulphonylureas. Side effects related to toxicity of the displaced drug would result, e.g. Mucositis/dirrahoea/BM suppression, bleeding, hypoglycaemia.

Question 11

What are the contra indications for NSAID use?

Answer 11

Patients with advanced CKD are advised to avoid NSAIDs since they can reduce renal blood flow, and hence GFR, further.

Question 12

Describe the situations in which NSAID therapy would be indicated.

Answer 12

NSAIDs can be used to manage mild-moderate pain associated with a number of conditions, as well as pain in isolation. This can include MSK pain and rheumatoid/osteoarthritis.

Question 13

Describe the elimination kinetics of NSAIDs

Answer 13

At low doses NSAID elimination kinetics are zero order, in which a constant proportion of the drug is removed by an enzyme system which is not saturated. Rate of removal is dose dependant.

At high doses NSAIDs can follow first order elimination kinetics, in which a constant amount of the drug is removed by an enzyme system which has become saturated. Increases in drug concentration can increase the risk of toxicity.

Question 14

Describe the role of prostaglandin receptors (EP) in inflammation.

Answer 14

EP1 receptor is a Gq system in which activation causes an increase in intracellular calcium, leading to increased firing at synaptic junctions and hyperalgesia. The threshold for action potential in reduced by inhibition of K channels and an increase in sodium conductance.

EP2 receptor is a Gs system in which activation causes vascular smooth muscle relaxation, leading to vasodilation.

EP3 receptor is a Gi system located centrally in the thalamus, involved in inducing fever in response to IL-1 signalling.

Question 15

Describe the administration and distribution of NSAIDs

Answer 15

NSAIDs can be administered orally as a tablet, but also as a transdermal patch for soft-tissue injury.

NSAIDs bind heavily to plasma protein in circulation, making their volume of distribution low.

Question 16

Describe the indications for aspirin prescription

Answer 16

Aspirin can be prescribed as an NSAID for the treatment of pain and inflammation. It can also be taken as primary or secondary prevention for cardiovascular disease, since it also acts as a thromboxane synthesis inhibitor acting to reduce platelet aggregation.

Question 17

Describe the mechanism of action specific to aspirin action in cardiovascular disease

Answer 17

Aspirin is an irreversible, competitive inhibitor of the COX-1 enzyme. COX-1 functions in platelets to generate thromboxane, a local mediator which promotes platelet aggregation. Reduction in platelet aggregation reduces the risk of thrombus formation and cardiovascular events such as MI.

Question 18

Describe some common drug drug interactions which may occur in NSAID use.

Answer 18

NSAIDs bind plasma protein heavily, meaning they can displace other drugs. Key drugs which can be displaced include warfarin (90%), sulphonylureas and methotrexate (50%). This interaction results in the toxicity of the displaced drug. The same effect can happen if multiple NSAIDs are taken at once.

Question 19

What are the indications for the prescription of paracetamol?

Answer 19

Paracetamol is a non-opiate analgesic drug which is not of the NSAID class, since it does not reduce inflammation. Paracetamol is commonly prescribed for isolated pain and/or fever.

Question 20

Describe the mechanism of action of paracetamol as an analgesic and an anti-pyretic.

Answer 20

Paracetamol is though to be an inhibitor of central and peripheral COX enzymes, with higher affinity for COX-2. Centrally, inhibition of COX results in a reduction in fever and pain through inhibition of prostaglandin synthesis. In addition, a metabolite of paracetamol can combine with arachanoic acid and inhibit the COX enzymes.

Question 21

Describe the toxicity concern related to the over-use of paracetamol.

Answer 21

Paracetamol taken in excess (i.e. 10g, 20 tablets) can result in irreversible liver toxicity. Paracetamol usually undergoes phase II metabolism with conjugation to sulphates or glucuronic acid in hepatocytes. However in excess this pathway becomes saturated (first order kinetics) resulting in alternative phase I metabolism. Here, paracetamol is processed by the cyt p450 system to NAPQI. NAPQI is highly toxic to hepatocytes since it acts as a nucleophile. It can be removed by conjugation to GSH, however GSH can quickly be used up and an accumulation of NAPQI can result. Loss of GSH will also cause oxidative stress in the liver.

Question 22

Describe the normal metabolic pathway by which paracetamol is removed.

Answer 22

Paracetamol at therapeutic doses is removed by the liver through phase II metabolism, involving the conjugation of sulphates or glucuronic acid. This form of the drug is more soluble, allowing its excretion via the kidney in the urine.

Question 23

How is a paracetamol overdose treated?

Answer 23

For the most effective treatment of paracetamol overdose the case must be identified within the first 4 hours and activated charcoal used to reduce absorption of the drug.

N-acetyl cysteine must be giving within the first 8 hours of overdose, which acts as a produce to the production of L-cysteine, the precursor of GSH. Replacing GSH in this way will reduce oxidative stress and help remove NAPQI. Treatment must be started within 48 hours or irreversible liver damage will result and a transplant required.