Session 7: NSAIDs and Opiates Flashcards
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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
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.
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.
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).
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.
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.
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.
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.
See eBNF
Describe how pain in subjective and the pain pathway
Pain is subjective
- Physiological (stimulation of nociceptors)
- Psychological (e.g. phantom limb pain, intractable pain (pain that is not stopped by any drug or treatment, sometimes no obvious physical reason for pain)).
- Pain is also associated with mood – positive mood, less likely to feel pain.
The pain pathway is described as: Nociceptor => Afferent Pain Fibres => Dorsal Root of the Spinal Cord => Inhibitory Interneurones in the SG <=> Thalamus and Primary Sensory Cortex (Inhibitory descending pathways)
Describe the Opioid Mechanism at the Cellular Level
Three major types of opioid receptors have been identified: Mu, Kappa and Delta.
- These are all G-protein coupled receptors.
- Of these the majority of therapeutic effects of exogenous opiates appear to be mediated via the Mu receptor.
- The endogenous opiates have varying degrees of interaction strength at these three sites.
Opioid Mechanism at the Cellular Level: binding to the opioid receptors results in effects at cellular levels to prevent the afferent pain signals.
- Binding at MOP receptors is linked to the increase in outward flux of K+ ions (hyperpolarisation) to reduce excitability
- Binding at KOP receptors is linked to decreased influx of Ca2+ via channels (directly decreasing intracellular Ca2+ concentration by acting on the Ca2+ channels)
- Binding to DOP receptors is negatively linked to decreased cAMP synthesis (indirectly reducing intracellular [Ca2+])
- The key effect is a fall in intracellular [Ca2+] => decreased release of neurotransmitter at the synapse
- Other roles that binding at this receptor may play in reducing pain are not yet fully characterised.
Describe the pharmacodynamics of opioids which are full agonists, partial agonists, mixed and anatagonists
Full agonists have a higher affinity for Mu receptors and include morphine, codeine and methadone.
Morphine is the gold standard opioid analgesic to which all new analgesics are compared to.
Importantly, both codeine and methadone are relatively ‘weak’ agonists compared to morphine and lack dependence.
Partial opioid agonists/antagonists were developed to have mixed effects at the three sites e.g. Nalbuphine has mixed agonist/antagonist effects: antagonist at Mu, partial agonist at Kappa and weak agonist at Delta.
The partial/mixed agonists can provide excellent analgesia without euphoria.
Full Antagonists: e.g. naloxone, predominantly bind at Mu receptors and are used to reverse potentially fatal agonist effects – most frequently respiratory depression.
