S8 NSAIDS Flashcards

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1
Q

The inflammatory response

A

A protective response to injurious stimuli to reduce risk of further damage to organism. Local injury results in an inflammatory signalling response provided by autacoids (e.g bradykinins, histamines, cytokines. Prostaglandins are eicosanoids), it is rapid, localised and has short half-lives.

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2
Q

Prostaglandins

A

• Synthesised from arachidonic acid, which itself is produced from cell memb phospholipids via phospholipaseA2. The pathway involves metabolism by COX enzymes;
o Phospholipidsarachidonic acid, which is metabolised by COX 1 to  PG G, which is metabolised by COX 2 to  PG H
o From PG H we can produce specific PGs, PG E most important in mediating inflammatory response.
• Prostaglandins bind to GPCRs, the action usually involves synergising effects of other autacoids
• Autacoid release following injury induces the expression of COX-2 and prostaglandins themselves synergise the action of other autacoids, which means there is a positive feedback loop mechanism
• PGs act as potent vasodilators. They induce pain, pyrexia and inflammation, which NSAIDs can prevent by inhibiting prostaglandins

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3
Q

Effects of NSAIDs

Anti-inflammatory

A

• Following injury, there’s increased release of PGE2 which results in swelling. NSAIDs inhibit COX leading to reduced PGE2 synthesis. This reduces inflammation but has little effect on the underlying condition

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4
Q

Analgesic

A

• Decreased synthesis of PGE2 in the dorsal horn leads to reduced neurotransmitter release, and therefore reduced excitability of pain relay neurones

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5
Q

Anti-pyretic

A

• Cytokines act on the hypothalamus to stimulate PGE2 release, this causes increased [Ca2+] and increased temp. NSAIDs inhibit hypothalamic COX2 enzymes, reducing PGE2 and therefore temp

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6
Q

Cox enzymes

A

Both convert arachidonic acid to PGH

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7
Q

COX 1

A

COX-1 is expressed in a wide range of tissues, PG synthesis by COX-1 has a major cytoprotective role (in gastric mucosa, renal blood flow, platelet aggregation). Due to PG t1/2 of 10 minutes, need constant synthesis of it. However, due to its constitutive expression, most of the ADRs of NSAIDs are caused by COX-1 inhibition

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8
Q

cox 2

A

COX-2 expression induced by inflammatory mediators (e.g bradykinin) and so is only expressed during injurious stimuli. Involved in renal homeostasis and tissue repair. The main therapeutic effects of NSAIDs come via COX-2 inhibition.
COX-1 and COX-2 do not work independently and PG synthesis from both enzymes is dependent on tissue and organ type.

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9
Q

NSAIDs

A

Main therapeutic effect of NSAIDs achieved via COX-2 inhibition (celecoxib), but most NSAIDS will competitively inhibit the COX-1 and COX-2, by occupying arachidonic acid binding sites. NSAIDs vary in affinity and efficacy to the COX-enzymes. However, all NSAIDs act as analgesics, anti-inflammatories, and antipyretics.

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10
Q

Pharmacokinetics

A
  • Given orally
  • Show linear pharmacokinetics (first-order elimination) within therapeutic dose range
  • Two groups; those with short half-lives <6hrs, and long >10hrs
  • Are heavily bound to plasma proteins
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11
Q

Uses

A

Anti-Inflammatories in MSK disorders. Analgesia (pain relief).

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12
Q

ADRs

A

Inhibition of COX-1 constitutive PG synthesis leads to many side effects;
• GI: COX-1 PGE2 usually stimulates protective mucus production and inhibits acid secretion, thus inhibition to PGE2 production will result in damage to the stomach. Can lead to ulceration, gastric bleeding.
• Renal: occurs in young/old, PGE2 maintains renal blood flow, if PGE2 reduced by NSAIDs then GFR shall drop, hypertension can also occur
• Vascular: NSAIDs cause increased risk of prolonged bleeding time, haemorrhage, and increased bruising
• Hypersensitivity: skin rashes (mild or severe e.g Stevens Johnson syndrome)
• Reyes syndrome: brain/liver injury

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13
Q

Drug interactions

A

NSAIDs can be used in combination with low-dose opiates, extending the range for treating pain and will also reduce the ADRs seen with opiates alone.
However, use of combination of NSAIDs can increase risk of ADRs, as they affect each other’s binding of plasma protein; this is important with NSAIDs and low-dose aspirin administration, as they compete for the COX-1 binding sites and interfere with the cardioprotective mechanism of aspirin.
Furthermore, the protein binding of NSAIDS can mean certain drugs are displaced by NSAIDs and may require dose adjustment if they want to prevent:
• ↑ Sulphonylurea – hypoglycaemia
• ↑ Warfarin – increased bleeding
• ↑ Methotrexate – hepatotoxicity

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14
Q

Aspirin

A
  • Only NSAID which irreversibly inhibits COX enzymes via acetylation (not by competitive blocking).
  • Gets converted to salicylate
  • Also acts as an as an anti-platelet as it prevents thromboxane A2 production
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15
Q

Paracetamol

A

Not an NSAID. Effective for mild analgesia and fever. Less ADRs than NSAIDs. Its therapeutic dose is 8x500mg a day, yet should be lowered for those with compromised hepatic function. Unknown action but appears to selectively inhibit COX 1&2 activity in CNS. First order PKs, half-life 2-4hrs.

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16
Q

Toxicology

A

In normal doses, paracetamol shows linear PKs. 90% enters phase II conjugation forming glucuronide and sulphate, rest enters phase I oxidation to produce NAPQI.
NAPQI is very reactive and toxic, it is detoxified by phase II conjugation with glutathione.

Single dose >10g is fatal. At high doses PK becomes zero order; phase II metabolism becomes saturated which leads to increase in phase I production of NAPQI. Increase in NAPQI will deplete the glutathione levels.

Unconjugated NAPQI is highly nucleophilic and binds with cellular macromolecules. Hepatic cell death occurs, and possibly renal failure.
Ideally, treatment for overdose should be done within 8 hours of overdose; can be IV N-acetylcysteine or oral methionine (to replenish glutathione levels).

17
Q

Rheumatoid arthritis

A

Chronic autoimmune condition that results in inflammation of the synovium leading to dissolution of cartilage and bone.
Pathogenesis
The chronic synovial inflammation is caused by T-cell activation and production of rheumatic factor which stimulates macrophages. Macrophages release many cytokines (e.g IL-1, TNF-α) which causes inflammation of the synovium.
Diagnosis:
Morning stiffness >1 hour, symmetrical arthritis of >3 joints, X-ray changes (e.g swan-neck)
Treatment
Aim to prevent joint destruction. Use Disease Modifying Anti-Rheumatic Drugs (DMARDs), which act to halt and may reverse the underlying processes. Immunosuppressant’s can be used, but avoid corticosteroids.

18
Q

smart Methotrexate

A
  • Mechanism: dihydrofolate reductase inhibitor (in malignant disease), inhibitor of T-Cell activation (in non-malignant disease e.g RA)
  • Administration: oral, IM, weekly dosing
  • ADRs: mucositis (give folic acid), pneumonitis, teratogenic. Toxicity monitoring is required
19
Q

Sulfasalazine

A
  • Mechanism: inhibit T-cell proliferation and IL-2 production, reduced neutrophil chemotaxis
  • Effective in treating RA and IBD
  • ADRs: myelosuppression, hepatitis, rash.
20
Q

Rituximab

A

B cell apoptosis

21
Q

immunosuppressant Corticosteroids

A
  • Used for immune suppression in RA, anti-inflammatory in asthma
  • Mechanism: bind to intracellular cytoplasmic receptors and promotes or inhibits gene transcription. Prevent IL 1&6 production and T cell activation
22
Q

Azathioprine

A
  • Used in RA, lupus (immune attack on healthy body tissues), vasculitis, IBD
  • Mechanism: It is a prodrug which is metabolised to 6-MP, reducing DNA and RNA synthesis. 6-MP is eliminated by TPMT.
  • ADRs: bone marrow suppression, increased risk of infection and malignancy
23
Q

Mycophenolate mofetil

A
  • Used in transplant immunosuppression and RA
  • Mechanism: a prodrug that acts to inhibit the enzyme inosine monophosphate dehydrogenase, which is required for guanine synthesis. The result is impaired B-cell and T-cell proliferation
  • ADRs: myelosuppression, vomiting, and diarrhoea
24
Q

Cyclophosphamide

A
  • Used in lupus, lymphoma, leukaemia
  • Mechanism: is a pro-drug that is metabolised by the CYP450 complex into its active drug form called 4-hydroxycylcophosphamide which cross-links DNA so it cannot replicate, this supresses T&B cell activity
  • ADRs: bladder cancer (due to toxic metabolite acrolein), lymphoma, infertility. Must monitor FBC.
25
Q

Biological Therapy

A

e.g adalimubab, infliximab
• Recombinant DNA technology produces substances identical to the body’s signalling proteins
• Monoclonal antibodies made specifically to block any substance, or target any cell type
• Receptor constructs (fusion proteins), based on a naturally occurring receptor, acting to block it

26
Q

Anti-TNF Drugs

A
  • Used in RA, IBD
  • Mechanism: bind to TNF preventing its action, this reduces inflammation, angiogenesis and joint destruction
  • ADRs: TB infection risk
27
Q

Calcineurin Inhibitors (Ciclosporin and Tacrolimus)

A
  • Used for transplant, dermatitis and psoriasis patients
  • Mechanism: Both ciclosporin and tacrolimus are active against T helper cells by preventing the production of IL-2 via calcineurin inhibition
  • ADRs: nephrotoxicity, hypertension
28
Q

Opioid analgesics

A

Main uses are as analgesics - relief of moderate to severe pain
Actions of Opioids include Psychoactive Central Effects, and peripheral effects involving ‘Gate theory’

29
Q

Gate theory

A
  • Pain transmitted to substantia gelatinosa (dorsal horn of spinal cord)
  • Neurotransmitter Substance P released
  • Opioids inhibit release of Substance P from nerve terminals
  • Inhibitory descending pathways from higher centres in the brain
30
Q

Endogenous Opioid Peptides:

A

Endorphins, Enkephalins, Dynorphins

31
Q

3 main opioid receptors

A

μ - mu (all opiates have high affinity for this)
δ - delta
Κ - kappa

32
Q

Mechanism

A

• Bind to opiate receptor (Gi), Inhibits adenylyl cyclase, Decreases cAMP (delta)
• Causes decreased presynaptic influx of Ca2+ (kappa), so reduced neurotransmitter release
• Reduced transmission of nociceptive (pain) impulses
o Also involved in postsynaptic hyperpolarization (increasing K+ efflux, mu)

33
Q

ADRs
naloxone, naltrexone, b
buprenorphine

A

Constipation, vomiting, Respiratory Depression, dependence (withdrawal symptoms) and develop tolerance (need higher dose)
Naloxone, Naltrexone = opiate antagonist – can be given in opiate toxicity, can reverse resp depression and treat dependence. Also methadone for withdrawal symptoms.
NB morphine is an agonist.
Buprenorphine is an example of an agonist and antagonist depending on receptor

34
Q

Types of opiates

A

Oral Codeine, Oral Tramadol, Morphine, Fentanyl patch

NB Codeinemorphine is via CYP2D6