Session 7: NSAIDs and Opiates Flashcards Preview

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Flashcards in Session 7: NSAIDs and Opiates Deck (47)
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1

Describe the inflammatory process - focus on the local response

The inflammatory process produced is a fundamental response to injurious stimulus, acting as a protective mechanism to reduce the risk of further damage to the organism.

    Injurious stimulus includes wide variety of noxious agents (physical/chemical injury, structural strain  - infections) and many diseases (autoimmune conditions).

    Local injury result in a signalling response; a wide range of local molecular mediators and signalling agents are used to show this tissue damage, known as autacoids, which includes the prostaglandins that NSAIDs act on, to reduce risk of further damage through continued use/activity.

    The local response is rapid, focussed, integrated (lasts as long as it needs too, systemic response is much slower)

    The autacoids include bradykinins, histamine, cytokines, leukotrienes, nitric oxide, neuropeptides and eicosanoids (which includes prostaglandins).

    The signalling overlap ensures robust inflammatory response. The key feature is localised release + short half lives, allowing fine control of the signalling response. 

2

What are prostaglandins derived from?

    Eicosanoids are 20-carbon phospholipid derivatives uses as signalling molecules. Variation in synthetic routes give rise to different classes. All eicosanoid classes are derived from Arachidonic acid which is cleaved from cell membrane phospholipids.

    Prostaglandin synthesis is part of the arachidonic acid metabolism pathway and a variety of prostaglandins can be produced from this pathway.

    Arachidonic acid is produced from phospholipids from the cell membrane mainly via phospholipase A2, which can then either enter the leukotriene pathway or the prostaglandin pathway.

Prostanoids include Prostaglandins (PGs), Prostacyclins and Thromboxanes. 

3

What is the Prostaglandin Pathway?

    The prostaglandin pathway involves metabolism by COX-1 and COX-2 enzymes to produce PGH (Prostaglandin H2). Once PGH has been produced, specific prostaglandins can then be produced from this, the most important of which is being PGE.

PGE is the most important in mediating inflammatory response: vasodilation, hyperalgesia (in the brain), fever and immunomodulation.

4

Describe expression of the COX-1 Enzyme

    COX-1 Isoform is constitutively expressed

COX-1 is expressed in wide range of tissue types (there all the time).

PG synthesis by COX-1 has major cytoprotective role in gastric mucosa, myocardium and renal parenchyma. It ensures optimised local perfusion – reduces ischaemia.

PG half-life is short (approximately 10 minutes) thus needs constant synthesis.

Due to its constitutive expression, most ADRs caused by NSAIDs effects are due to COX-1 inhibition.

5

Describe expression of the COX-2 enzyme

    COX-2 Isoform Expression is Induced by Injurious Stimuli

COX-2 expression is induced by inflammatory mediators such as Bradykinin.

COX-2 appears to be constitutively expressed in parts of the brain and kidney.

Main therapeutic effects of NSAIDs occur via COX-2 inhibition.

COX-1 and 2 not work independently and PG synthesis with both enzymes depends on tissue and organ type. 

6

Describe the binding of prostaglandins and what exactly do prostaglandins do?

    Prostaglandins bind to GPCRs with the specific action of the binding depending upon the receptor types (e.g. for PGE, there are four main types of EP1-4).

    Prostaglandin: inflammatory response mediators. Autacoid release will induce the expression of COX-2 and often the action includes synergising the action of other autacoids, which means there is a positive feedback loop with the prostaglandin production.

  • Range of autacoids and prostanoids released post injury especially PGE2, also PGD2.
  • Released from local tissues and blood vessels.
  • Autacoid release also induces expression of COX-2.
  • Synergise with other autacoids – Bradykinin/Histamine
  • PGs act as potent vasodilators but don’t increase capillary permeability directly – synergise permeating effects of Bradykinin/Histamine. 

7

How do prostaglandins act to induce pain and pyrexia by sensitising peripheral nociception?

Painful stimuli carried by afferent ‘C’ fibres. Following trauma/injury, surrounding tissues and neurones synthesise PGEs – PGE2 in particular. Other autacoids are released – notably bradykinin.

PGE2 can bind to EP1 (G(alpha)q-type GPCR) in C-fibres, which act to inhibit K+ channels, increase Na+ channel expression and increase neuronal sensitivity to bradykinin. This combination of effects results in an increased C-fibre activity. There is also action via a rise in intracellular [Ca2+] levels causing increase in neurotransmitter release.

PGs may also activate previously silent ‘C’ fibres.

8

What is meant by Peripheral Sensitisation?

EP I binding leads to increased C fibre activity

EP I is a Gq GPCR activation, leading to increased intracellular Ca2+ => increased neurotransmitter release

Other autacoids involved lead to increased sensitivity. 

9

How do prostaglandins induce pain and pyrexia by sensitising Central Sensation

Increased sustained nociceptive signalling peripherally results in increased cytokine levels in dorsal horn cell body. This causes increased COX-2 synthesis and increased PGE2 synthesis.

PGE2 can bind to local EP2 (G(alpha)s-type GPCR) in the dorsal horn of the spinal cord. The rise in cAMP and subsequent activation of Protein Kinase A causes a reduction in glycine receptor binding affinity (as glycine acts as an inhibitor of neuronal activity). This removal of glycinergic inhibition helps increase sensitivity + discharge rate of secondary interneurons, leading to increased pain reception.

10

How do prostaglandins induce pyrexia?

In infected/inflammatory states, bacterial endotoxins stimulate macrophage release of IL-1.

IL-1 within the hypothalamus (via induction of COX-2?) stimulates PGE2 release.

PGE2 acts on EP3 (G(alpha)i-type GPCR) which causes a fall in cAMP which eventually causes increase in intracellular [Ca2+] levels in the neurones regulating temperature. This results in both increased heat production and reduced heat loss. 

11

What are the main therapeutic effects of NSAIDs?

NSAIDs are a very widely used therapeutic globally and encompass ~50 drugs (significant structural heterogeneity). The principle action is key enzymes in prostaglandin synthesis. The NSAIDs’ main therapeutic effects include:

   Analgesia

   Anti-inflammation

    Anti-pyresis in fever

12

Describe COX inhibition and selectivity

The main therapeutic effect is achieved via COX-2 inhibition, whereby the majority of NSAIDs will competitive inhibit the COX-1 and COX-2 arachidonic acid binding sites (notable exception Aspirin) yet different NSAIDs have wide variation in affinity, efficacy and COX-1/COX-2 selectivity.

    Occupation of COX-1/2 hydrophobic channel by NSAIDs competes with AA site occupation.

The variation in molecular structure in newer NSAIDs is related to their selectivity, but most established NSAIDs are derivatives of carboxylic acid.

Cyclo-oxygenase (COX) enzyme inhibition:

  •     The known primary mode of action is inhibition of COX-1 & COX-2.
  •     A range of membrane phospholipids can be converted to yield arachidonic acid. This serves as the precursor for a number of very important signalling agents, collectively known as eicosanoids. These include the prostanoids: prostaglandins, prostacyclins thromboxanes
  •     Leukotrienes are also produced but by a different enzymatic pathway.

COX-1/COX-2 Specificity

  •     NSAIDs exhibit a range of selectivity for the two forms. Generally NSAID action on COX-1 is rapid and competitive, on COX-2 is slower and often irreversible. 

13

How do NSAIDs cause Analgesia, Anti-inflammation and Anti-pyresis (in fever)?

What determines NSAID choice?

Analgesia

  •     By reducing synthesis of prostaglandins that sensitise nociceptors to inflammatory mediators, thought to reduce headache pain by cerebral vasodilation mediated by prostaglandins.
  •     May also have a secondary effect on prostaglandin facilitation of afferent pain signal in spinal cord dorsal horn neurones.

Anti-inflammation

  •     Along with prostaglandins, there are a number of other mediators orchestrating inflammatory response.
  •     Therefore NSAIDs will have an effect proportionate to prostaglandin involvement (mainly COX-2)
  •     Primarily reduce erythema, swelling and pain response associated with swelling.

Anti-pyresis

  •     Fever due to bacterial endotoxins triggering macrophage release of endogenous pyrogen IL-1. This stimulates hypothalamic production of PG-E that elevate set point on central ‘thermostat’.
  •     NSIADs reduce PG-E synthesis.

Often dominant disease state and individual patient response determine physician choice. 

14

Understand therapeutics/ADRs in terms of action on COX-1 and COX-2 ADRs. What is a notable exception?

COX-1 Inhibition: COX-1 is constitutive in the body (expressed in a wide range of tissue types) and blocking prostaglandin synthesis here appears to result in most NSAID ADRs.

COX-2 inhibition: COX-2 is induced in inflammatory cells following activation by cytokines. The resulting prostanoids act as inflammatory response mediators. Therefore COX-2 inhibition is considered as the site where NSAIDs exert their therapeutic anti-inflammatory/analgesic effect.

Aspirin is a notable exception in that it irreversibly inactivates COX-1 (via acetylaition – i.e. not competitive blocking) and this provides the basis for its effects on platelets.

  •     Its half-life < 30 minutes before it is converted to salicylate. 

15

What are the consequences of aspirin overdose?

Aspirin stimulates the respiratory centre, which results in respiratory alkalosis (hyperventilation elevates the blood pH). Compensatory mechanisms result in metabolic acidosis. A fall in serum pH indicates serious poisoning.

Aspirin overdose also interferes with carbohydrate, fat and protein metabolism and oxidative phosphorylation => increase in lactate, pyruvate and ketone bodies all contribute to acidosis.

As platelet cyclooxygenase is inhibited and thromboaxane A2 production is blocked, there is decreased platelet aggregation and petechiae may be present.

Aspirin may also affect mucus production => acute erosive gastritis => GI bleeding

16

Appreciate the use of NSAID as Analgesics Anti-inflammatories and Antipyretics

NSAIDs constitute a large group of drugs used to treat mild to moderate pain in isolation (e.g. headache, menstrual pain).

They are also used to treat chronic pain in combination with inflammation arising from joint disease such as rheumatoid arthritis.

They are also commonly used for treating acute inflammation and pain arising from soft tissue injury.

Anti-inflammatories

  •     Very wide use in musculoskeletal disorders – rheumatoid/osteoarthritis

Analgesia:

  •     Mild to moderate pain though less effective than opiates – better ADR profile.
  •     Moderate pain accompanies many disease states – very common with many medical procedures
  •     NSAID universal use in hospitals/OTC

NSAID Group ADRs at therapeutic levels are mainly due to COX-1 inhibition.

Long term use in elderly particularly associated with iatrogenic morbidity and mortality. 

17

Recognise the differences in NSAID pharmacokinetics

Typically given orally but many topical preparations for local delivery to injured soft tissue (e.g. ‘Wintergreen’, ‘Fiery Jack’, deep heat spreay).

Most NSAIDs generally show first-order (linear) elimination kinetics, dividing into those with a short half life (<6 hours) e.g. Ibuprofen, (half life = 2 hours); and those with a long half life (>10 hours) e.g. naproxen (half life = 14 hours),

Aspirin exhibits dose dependent kinetics low doses – first order (half life = 4 hours); at high doses (> 12 x 300mg tablets) aspirin exhibits zero-order kinetics.

NSAIDs are heavily bound to plasma proteins (90-99%) via weak ionic associations, and can act to displace other plasma protein binding drugs.

18

What are the GI ADRs associated with NSAIDs?

GI effects: PGE2 is cytoprotective - is involved in protection of gastric mucosa – inhibits acid secretion and stimulates mucosal production, promotes mucosal blood flow.

    PGE2 inhibition increases mucosal permeability and decreases mucosal blood flow and protection.

    NSAIDs can cause damage to stomach directly on ingestion and systemically.

    Clinical burden due to ulceration, haemorrhage and even perforation seen with long term high dose elderly users. GI ADRs occur in approximately 35% users. Often asymptomatic.

    ADRs include varying degrees of stomach pain, nausea, heartburn, gastric bleeding and ulceration.

    NSAIDs especially long term have high incidence of GI ADRs between 10-30%.

Offset GI ADRs (long term, elderly) with PPIs or misoprostol (prostacyclin analogue).

19

What are the renal ADRs associated with NSAIDs

    Can also occur in susceptible individuals (e.g. HRH individuals or hypovolaemia – consider heart failure, renal disease, hepatic cirrhosis)) although therapeutic dosage in otherwise healthy patients do not cause problems.

    Reversible reduction in GFR and perfusion of the kidney occurs as a result of PGE2 and PGI2 inhibition (vasoconstriction occurs) – normally PGE2 and PGI2 maintain renal blood flow. Decreased GFR can lead to further risk of renal compromise.

    Na+/K+/Cl- and H2O retention follow with increased likelihood of hypertension (hence need for monitoring).

Neonates, the elderly and patients with compromised renal, hepatic and cardiac function or reduced blood volume are at particular risk. 

20

What other ADRs, apart from GI and renal, are associated with NSAIDs?

    Include skin reactions (rashes can occur up into 15% for some NSAIDS, usually mild but can be serious – Stevens Johnson Syndrome. However this syndrome can occur with other drug groups not just NSAIDs – hypersensitivity response.

    Asthmatic bronchospasm (10% incidence) - hypersensitivity

    Vascular: Prolongation of bleeding time and increased bruising haemorrhage due to platelet inhibition may also present problems, however this action forms the basis for the widespread use of aspirin as a cardiovascular protectant.

    Aspirin is also associated with risk of Reye’s Syndrome in children  (rapidly progressive encephalopathy that can especially cause brain and liver damage and hyperammonia) – usually in viral infections treated with aspirin. Incidence less than 1/year.

21

Describe Selective COX-2 Inhibitors

    The incidence of side effects with mixed COX-1 and 2 inhibition lead to the development of selective COX-2 inhibitors such as Rofecoxib, Celecoxib,

    Unfortunately clinical experience with these newer drugs did not bear out their initial promise especially as their use was associated with an increased risk of hypertension, cardiac and renal failure.

    Consequently, the further development of this class of drugs is in question.

    US/EU approval for short term use only. 

22

What are important drug-drug interactions to consider when using NSAIDs?

    Due to their very wide availability, some patients may already be self-medication with NSAIDs.

    It is therefore appropriate to question patients prior to prescription to name other drugs they may be taking.

    Aspirin also interacts with warfarin displacing it from plasma protein to increase the active free concentration. They can also both affect protein aggregation.

    Additionally, NSAIDs can interact with ACE inhibitors and attenuate their action, (by blocking the production of vasodilating prostaglandins)

    Therapeutically, NSAIDs can be used in combination with low-dose opiates, extending the therapeutic range for treating pain and will also reduce the ADRs seen with opiate use alone. They act by different mechanisms to extent therapeutic range.

However, use of a combination of multiple NSAIDs can also increase the risk of ADRs as they affect on another’s binding of plasma protein due to competition for plasma protein binding sites (majority of protein bound); this is especially important in NSAIDs and low-dose aspirin administration, as they will compete for the COX-1 binding sites and interfere with the cardioprotective mechanism of aspirin.

- Combination of NSAIDs often occurs due to self-medication with NSAIDs. 

23

What kind of drugs do NSAIDs displace? And describe drug monitoring re NSAIDs?

    Moreover, the protein binding of NSAIDs can mean certain drugs are displaced (competitively) by NSAIDs and may require dose adjustment if they want to prevent changes in PK and D:

  • Increased [Sulphonylurea] => hypoglycaemia
  • Increased [Warfarin] => increased bleeding
  • Increased [Methotrexate} => wide range of serious ADRs.

Drug Monitoring

    Acute use of NSAIDs unless in a vulnerable patient group should not merit monitoring.

    However, close attention should be paid to those on chronic NSAID therapy who deserve regular review of patient GI symptoms.

    Renal function may also require monitoring. 

Drug Interactions and Monitoring: Paracetamol is often given with weak opiates to enhance its effect on moderate pain e.g. co-codamol. The caveats about concomitant use with NSAIDs also applies to a wide range of paracetamol-containing products (e.g. Lemsip). Unless a patient is on long term therapy, hepatic and renal function is not normally monitored. 

24

Describe the use of aspirin as an NSAID and its pharmacokinetics

Aspirin is used as reference NSAID for efficacy and ADR severity.

Still in very widespread use especially acute self-medication.

Relatively higher long-term risk of ADRs.

It is the only NSAID to irreversibly inhibit COX enzymes by acetylation.

It has a unique PK profile as its half life is less than 30 minutes – rapidly hydrolysed in plasma to salicylate. 

    Salicylate PKs are dose dependent. At lower doses first order (half life is approximately 4 hours).

    At higher doses (approximately 12x300mg tablets/day) zero order kinetics apply.

    Widespread use as cardioprotective (75mg)

    Increasing trial evidence as prophylactic for GI/breast other cancers – trials continue.

25

What are other therapeutic uses of aspirin?

    Athero-thrombotic disease: the use of low dose (75mg) Aspirin in reducing platelet aggregation is very widespread in treating a range of conditions with a vascular component

  • Aspirin irreversibly inhibits the COX-1 activity that drives pro-aggregative activity in both platelets and the vessel wall (prevents thromboxane A2 production) to reduce the likelihood of thrombotic formation.
  • Other NSAIDs share this activity.

    GI Cancer Prophylaxis: there is evidence also that aspirin may reduce the risk of GI cancers of the colon rectum and possibly upper GI. This is because these cancers synthesise PGE2 which promotes tumour growth – clinical trials are ongoing.

26

Why is Paracetamol considered a NOAD?

Paracetamol is chemically related to other NSAIDs but lacks the group anti-inflammatory properties. It is unique non-NSAID – a NOAD.

For mild to moderate cases of pain or fever it remains the first agent of choice as it is very effective (analgesic and antipyretic) and at therapeutic doses, has a much better ADR profile than other NSAIDs. It appears to selectively inhibit COX activity in the CNS by an as yet uncertain mechanism.

  •     Weak COX-1/COX-2 inhibitor
  •     Considered to primarily act in CNS possibly on a COX-3 iosform
  •     Metabolite in CNS can combine with arachidonic acid to form a substrate to block binding with COX-1/COX-2 – inhibiting activity.

It is an agent of choice for moderate pain and fever. 

27

Describe the therapeutic doses, pharmacokinetics and ADRs of paracetamol

At therapeutic doses i.e. normally no more than 8x500mg tablets or 4g in divided doses/day.

  •     This is lowered to 2g/day in chronic alcoholics or those with compromised hepatic function.
  •     At these levels side effects are uncommon although chronic use at these levels may result in minor hepatic insult.

 Pharmacokinetics/ADRs:

  •     Given orally plasma peaks with 30-60 mins and normally has a half life of 2-4 hours (first order in healthy patients, normal doses)
  •     However, with toxic doses of 10-15g, or about 20-30 tablets, it can deleteriously affect its own half life by causing serious hepatic deficit.
  •     It has been associated with presbycusis (age-related hearing loss)

28

Describe the pharmacokinetics in paracetamol toxicity

In normal doses, paracetamol shows linear PKs. 90% enters phase 2 metabolism directly (60% glucoronidation and 30% sulphonation) whilst the main 10% enters phase 1 oxidation to produce NAPQI.

A single dose of only 10g (20 tablets) is potentially fatal and often hepatotoxic. At high doses of paracetamol, the pharmacokinetics becomes non-linear (zero-order) as first step phase II metabolism is saturated. This then leads to increased Phase I production of NAPQI. Second step Phase II conjugation of NAPQI with glutathione is rate-limited and thus also saturated.

The toxic mechanism involves saturation (i.e. zero-order kinetics) of the Phase II enzymes that normally metabolise paracetamol. The drug is then instead metabolised by Phase 1 CYP450 2E1. The highly reactive intermediate metabolite (NAPQI) of paracetamol is normally conjugated with glutathione.

    NAPQI is very reactive and toxic, as it can act as an oxidiser, so is detoxified by phase II conjugation with glutathione – this step is also linear pharmacokinetics but is limited by the availability of glutathione. 

29

What happens if glutathione stores are deleted in paracetamol overdose?

If glutathione reserves are depleted due to the very large dose of paracetamol, this leads to the reactive intermediate exerting its toxic effect. Unconjugated NAPQI is highly reactive nucleophilic and binds with many cellular macromolecules (including proteins, mitochondrial proteins, DNA and RNA) that results in loss of hepatic cell function and subsequent hepatic nercrotic cell death, as well as potential for causing renal failure.

    This additionally increases a systemic burden as the liver is less able to cope with the normal levels of free radicals generated by the body.

    These result in further apoptotic damage and further compromise of hepatic function

    Paediatric and elderly patients are at increased risk of hepatic and renal failure.

    In UK, paracetamol overdose is the most common cause of hepatic failure (non-self harm).

30

How should paracetamol overdose be treated?

Ideally overdose should be treated as soon as possible and guided by blood levels of drug with agents such as IV N-acetylcysteine or oral methionine that increases glutathione levels.

    Time-dependent: delayed hepatoxic effects peak 72-96 hours post ingestion.

    Ideally overdose should be treated within eight hours of overdose.

If seen within 0-4 hours, activated charcoal orally can reduce uptake by 50-90%.

Between 0-36 hours, agents such as IV N-acetylcysteine or oral methionine (if NAC cannot be given properly) can be used which act to increase glutathione levels. Ideally treat within the first 12 hours.

    Overdose can still be treated within 24-28 hours to offset liver damage, but if this therapeutic window is missed, then the patient is very likely to die of liver failure.

    Renal tubular necrosis and hypoglycaemic coma may occur secondarily.

    Patients whose plasma-paracetamol concentrations are on or above the treatment line should be treated with N-acetylcysteine by intravenous infusion (or if acetylcysteine cannot be used, with methionine by mouth, provided the overdose has been taken within 10-12 hours and the patient is not vomiting). The prognostic accuracy after 15 hours is uncertain, but a plasma-paracetamol concentration on or above the treatment line should be regarded as carrying a serious risk of liver damage. 

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