Session 8 Flashcards
- Recognise the central role of arachidonic acid in prostanoid synthesis
- Understand the general pharmacology of NSAID action on COX-1 on COX-2 inhibition
- Understand therapeutics / ADRs in terms of action on COX-1 and COX-2
- Appreciate the use of NSAID as analgesics, anti-inflammatories and antipyretics
- Recognise the differences in NSAID pharmacokinetics
- Describe the major ADRs / drug interactions associated with NSAIDs
- Understand the mode of action of NSAIDs on platelet function exemplified by aspirin
- Appreciate the special case of paracetamol as an analgesic / antipyretic
- Recognise the main features of paracetamol overdose and toxicity.
Non Steroidal Anti-Inflammatory Drugs (NSAIDs):
- Principle action - ?
- Three primary therapeutic effects:
- key enzymes in prostaglandin synthesis
- Analgesia
Anti-Inflammatory
Antipyretic
The Inflammatory Response
- Fundamental response of body to injurious stimuli - includes wide variety of noxious agents. Give examples:
- Why have it?
- Physical /Chemical Injury
- Structural Strain
- Infections Many Diseases
- Autoimmune Conditions - Normally protective response to reduce risk of further damage to organism
- Alerts body through signalling pain - reduces risk of further damage through continued use/activity
- Normally protective response to reduce risk of further damage to organism
Autacoids Signal the Inflammatory Response
- Diverse range of local molecular mediators and signalling agents employed - the Autacoids * including?
- Signalling overlap ensures robust inflammatory response
- Key feature of autacoids is?
- Bradykinins
- Histamine
- Cytokines
- Leukotrienes
- Nitric Oxide
- Neuropeptides
- Eicosanoids – Includes Prostaglandins
2.
- localised release + short half lives allows fine control of the signalling response
Recognise the central role of arachidonic acid in prostanoid synthesis LO
- What is the structure of Eicosanoids and their use?
- Variation in synthetic routes give rise to different classes of Eicosanoids: \
- All Eicosanoid classes derived from?
- 20 C phospholipid derivatives
- signalling molecules
- 20 C phospholipid derivatives
- Prostanoids: Prostaglandins (PGs) Prostacyclins Thromboxanes
- Leukotrienes
- Prostanoids: Prostaglandins (PGs) Prostacyclins Thromboxanes
- Arachidonic Acid which is cleaved from cell membrane phospholipids
Recognise the central role of arachidonic acid in prostanoid synthesis LO
Draw a diagram showing the synthesise of PGs
How is COX-1 Isoform expressed?
- COX-1 expressed in ?
- PG synthesis by COX -1 has major cytoprotective role of?
- What is the t1/2 for PG ?
- Due to its constitutive expression, most ADRs caused by NSAIDs effects are due to ?
Constitutively Expressed
- wide range of tissue types
- Gastric mucosa
+Myocardium
+ Renal parenchyma - Ensures optimised local perfusion – reduces ischemia
- short = 10 mins - need constant synthesis
- COX-1 inhibition
- How is COX-2 Isoform expressed?
- COX-2 expression induced by?
- COX-2 appears to be constitutively expressed in parts of the ?
- Main therapeutic effects of NSAIDs occur via ?
- COX-1 and 2 do not work independently and PG synthesis with both enzymes depends on tissue and organ type
- Induced by Injurious Stimuli
- inflammatory mediators such as Bradykinin
- brain and kidney
- COX-2 inhibition
5.
Differences in COX-1 and COX-2 tunnel for catalysing Arachidonic Acid
???
Understand the general pharmacology of NSAID action on COX-1 on COX-2 inhibition LO
Differences in COX-1 and COX-2 tunnel for selective inhibition by different NSAIDs
1 - first time you have sex ur tight
2 time u r baggy
aspirin is small! Can fit into both
aspirin for ALL
Prostaglandins: General Pharmacology
- Prostaglandins bind with ?
- Specific actions depends on ?
- For PG ‘E’ at least four main types: ?
- Often action includes?
- GPCRs
- PG receptor types
- EP 1-4
- synergising effects of other autacoids – eg. Bradykinin/Histamine
Prostaglandin Pharmacology - Inflammatory Response Mediators
- Range of autacoids and prostanoids released post injury esp. ?
- Released from ?
- Autacoid release also induces ?
- Synergise with other autacoids – e.g.
- Action of PGs?
- PGE2 - also PGD2
- local tissues and blood vessels
- expression of COX-2
- Bradykinin/Histamine
Prostaglandin release following injury.
- Function of EP2 receptor?
- Function of EP1 receptor?
- Gs -> vasodilation
- Gq -> peripheral nociception
2 veSSels
Prostaglandin Pharmacology- Pain 1: Sensitising Afferent Nociception - EP1
How do EP1 receptors sensitise harmful stimuli?
- Painful stimuli carried by afferent ‘C’ fibres (non myelinated)
- Following trauma/injury surrounding tissue and neurons synthesise PGs - PGE
- Other autacoids released - notably Bradykinin
- PGE2 binds with ‘C’ fibre neuronal EP1 GPCR receptor
Pain 1: Sensitising Peripheral Nociception - EP1
- GPCR activation results in:
- PGs may also activate ?
- Increased neuronal sensitivity to Bradykinin
- Inhibition of K+ channels
- Increased Na+ channels sensitivity
- In combination - these act to increase ‘C’ fibre activity
- Increased neuronal sensitivity to Bradykinin
- previously silent ‘C’ fibres
Peripheral Sensitisation (at synapse?)
- What effect does EP 1 binding have on C fibres?
- What type of receptor is EP1? What does binding to the receptor result in?
- INCRESE ‘C’ fibre activity
- Gq GPCR
INCREASE intracellular Ca2+
Increase Neurotransmitter release
Other autacoids involved INCREASE sensitivity
- Explain what this graph is showing
- What is the meaning of:
Allodynia
Hyperalgesia
Explain how we Pain Sensitise Central Nociception
- Increased sustained nociceptive signalling peripherally result in INCREASE cytokine levels in dorsal horn cell body
- This causes INCREASE COX-2 synthesis & INCREASE PGE2 synthesis
- PGE2 then acts via local GPCR EP2 receptor (Gs Type)
- This increase sensitivity + discharge rate of secondary interneurones
- One aspect is removal of glycinergic inhibition
- What are the effects of PGE2 when it binds to EP2 receptor ?
- Leading to what overall effect?
- Increase cAMP increase PKA
- Decrease Glycine Receptor Binding Affinity
- Increase Pain perception
- Increase cAMP increase PKA
- Increased pain perception
Sensitisation in dorsal horn by PGE2
How do prostaglandins result in pyrexia?
Pyr3xia – EP3
+ In infected /inflammatory states bacterial endotoxins stimulate macrophage release of IL-1
+ IL-1 within the hypothalamus (via induction of COX-2?) stimulates PGE2 synthesis
+ PGE2 via EP3 receptor - Gi type GPCR
+ Results in both INCREASE heat production & DECREASE heat loss
NSAIDs: Therapeutic Effects - General
1 Main therapeutic effects achieved via ?
- Pharmacological action for nearly all NSAIDs via ?
- Occupation of COX-1 / 2 hydrophobic channel by NSAID competes with ?
- With = 50 different NSAIDs wide variation in ?
- COX-2 inhibition
- competitive inhibition of COX-1 and COX-2
- AA site occupation
- Affinity, Efficacy and COX-1/COX-2 selectivity (see later)
NSAIDs: Therapeutic Effects General
- Main therapeutic effects achieved via?
- Nearly all have therapeutic efficacy as?
Often dominant disease state and individual patient response determine physician choice
- COX-2 inhibition
- analgesics, anti- inflammatories, and antipyretics
NSAIDs :Therapeutic Effects Pharmacokinetics
- Administration?
- Linear pharmacokinetics within therapeutic dose range (see Aspirin/Paracetamol)
- T1/2s two groups: ?
- Free or bound drug?
- Typically given orally but many topical preparations for soft tissue injury
2.
- T ½ < 6hrs
T ½ > 10 hrs
- Many heavily bound to plasma protein 90-99%
Appreciate the use of NSAID as analgesics, anti-inflammatories and antipyretics LO
NSAIDs : Main Therapeutic Uses
- When is NSAIDS used as Anti-Inflammatories?
Analgesia
- What type of pain is it used for? Why is it better than other pain relief?
- When used?
- Very wide use in Musculoskeletal Disorders – Rheumatoid/Osteoarthritis
- 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
- Moderate pain accompanies many disease states very common with many medical procedures.
Describe the major ADRs / drug interactions associated with NSAIDs LO
NSAIDs: ADRs
- What mechanism of action of NSAIDS result in ADRS?
- Long term use in elderly - particularly associated with?
- Major ADRs seen in ?
- Renal ADRs occur in compromised individuals with ?
- Inhibition of COX-1 constitutive PG synthesis
- iatrogenic morbidity and mortality
- stomach /GI tract
- HRH or hypovolaemia
- Heart failure
- Renal disease
- Hepatic cirrhosis
NSAIDs: GI ADRs
- GI ADRs in = ?
- Specifically what are the GI ADRs?
- Gastric COX-1 PGE secretion throughout GI tract, stimulates ?
- NSAIDs especially long term - have high incidence of GI ADRs between 10-30%
- Offset GI ADRs (long term) with PPIs or misoprostol 2
- 35% users. Often asymptomatic
- varying degrees stomach pain, nausea, heartburn, gastric bleeding, ulceration
- cytoprotective mucus secretion throughout GI reduce acid secretion and promote mucosal blood flow
4.
NSAIDs: Renal/Renovascular ADRs
- Renal ADRs - in HRH compromised (esp neonates/elderly) fgdue to renal perfusion blood flow DECREASED
- PGE2 & PGI2 maintain renal blood flow
- If reduced by NSAIDs then GFR DECREASED - further risk of renal compromise - dose and use dependent risk INCREASE
- Na+/K+/Cl- and H2O retention follow with increased likelihood of hypertension
1.
2.
3.
4.
NSAIDs: Other ADRs
- Vascular ADRs?
- Hypersensitivity ADRS?
- What syndrome can this result in? Describe this syndrome?
- Risk INCREASE bleeding time INCREASE bruising haemorrhage
- • Skin rashes (15% for some NSAIDs) usually mild
Rare but very serious - Stevens Johnson syndrome*
• Bronchial asthma - Rx care in asthmatics (10% incidence)
- Reyes Syndrome (paediatric)
• Rare serious brain/liver injury – usually in viral infections treated with aspirin risk of damage.
UK Incidence 2010 <1/yr vs 1980s 40/yr
What is this image showing?
Stevens Johnson Syndrome - Severe examples
Immune-complex-mediated hypersensitivity disorder
Compromised hepatic function
Rash - skin mucous membranes
NSAIDs – Specific COX-2 Inhibitors
- Large research effort put into developing highly selective COX-2 inhibitors e.g. ?
- Theoretically overcome ADRs due to COX-1 inhibition with equal efficacy to standard NSAIDs
- Explain the ADRs for specific COX-2 inhibitors
- Rofecoxib, celecoxib,
2.
- Not completely free of GI ADRs
Clinical trials show significant increase of cardio- vascular ADRs with long term use - US/EU approval for short term use only
NSAIDs: Drug Interactions Therapeutic Pharmacodynamic
- Why do we use NSAIDS in combination with low dose opiates?
- What different mechanisms do NSAIDS + opiates act to extend range?
- What does combined NSAIDS and opiates do to ADRs Reduces ADRs seen with opiates alone.
- extends therapeutic range for treating pain
- see Opiate Lecture
NSAIDS in Combination
- How do NSAIDs given in combination effect ADRs?
- NSAIDs together can affect each others PK/PDs due to ?
- What happens when we give NSAIDs + low dose Aspirin
- increase risk of ADRs - often occurs due to self medication with NSAIDs
- competition for plasma protein binding sites - many NSAIDs heavily bound - up to 90-99%
- Compete for COX-1 binding sites - may interfere with cardioprotective action of Aspirin
NSAIDs: Drug Interactions NSAID protein binding can affect PK/PDs
- Highly protein bound drugs affected by NSAIDs include: (3)
- Competitive displacement of these drugs may require dose adjustment to avoid changes in PK and PD. I.e. what happens to the levels of these drugs?
- Sulphonylurea
+ Warfarin
+ Methotrexate
- Sulphonylurea - Hypoglycaemia
+ Warfarin – Increased Bleeding
+ Methotrexate – Wide ranging serious ADRs
• Understand the mode of action of NSAIDs on platelet function exemplified by aspirin LO
Aspirin : The First NSAID
+ Aspirin used as reference NSAID for efficacy and ADR severity
+ Still in very widespread especially acute self medication. Relatively higher long term risk of ADRs
- What is the effect of aspirin on COX enzymes?
- Unique PK profile. What is its half life?
- Salicylate PKs dose dependent. What is its half life?
- Aspirin use?
- Only NSAID to irreversibly inhibit COX enzymes by acetylation
- T½ less than 30 minutes rapidly hydrolysed in plasma to salicylate
- At lower doses first order t½ ≈ 4hrs
At higher doses ≈ 12x300 mg tablets/day zero order kinetics apply
- cardioprotective (75 mg)
Increasing trial evidence as prophylactic for GI/breast other cancers – trials continue
Give an example of a unique non NSAID Non-Opiate Analgesic
Paracetamol
Paracetamol: A Unique Non NSAID Non-Opiate Analgesic
- Paracetamol is a unique ‘non NSAID’, why?
- Very effective for?
- At therapeutic doses has much better ADR profile than other NSAIDs
- Use?
- Therapeutic doses:
- no anti-inflammatory action - more of a NOAD
- mild/moderate analgesia & fever
3.
- moderate pain and fever
- 8 x 500 mg tablets/day
Paracetamol: Pharmacology
- Mechanism?
- PKs first order in healthy patient t½ ≈
- Currently unknown mechanism – weak COX-1 / COX- 2 inhibitor
- Considered to primarily act in CNS - possibly on TRP channels ??
- Metabolite in CNS can combine with AA to block binding with COX-1/COX-2 ??
- Currently unknown mechanism – weak COX-1 / COX- 2 inhibitor
- 2-4 hrs
• Caution ! in those with compromised hepatic function or alcoholics
Paracetamol:Toxicology 1
- Normal doses - Linear PKs
- How is it metabolised?
- What is NAPQI? How is it metabolised?
1.
- Mainly use Phase II Conjugation – (Glucoronide 60% & Sulphate 30%)
Some Phase 1 Oxidation – NAPQI *10%
- Very reactive and toxic
- NAPQI at normal doses is detoxified by Phase II conjugation with Glutathione
- This detoxification step is also linear BUT limited by availability of Glutathione.
* N – Acetyl - p - Benzoquinone – Imine: just say NAPQI !
Paracetamol: Toxicology II
- What dose of paracetamol is fatal?
- At high doses Paracetamol PKs become?
- What happens to the metabolism of parecetomal to go from in the therapeutic window to toxic?
- Single doses > 10 g (20 tablets) potentially fatal!
- zero order
- First step Phase II metabolism saturated
- Then leads to INCREASE Phase I production of NAPQI
- Second step Phase II conjugation of NAPQI with glutathione rate limited – also saturated
- First step Phase II metabolism saturated
NAPQI
NAPQI has spare electron groups on the = O atoms and =N- atoms !
Clinical significance?
Loves positive charges and will react !
Paracetamol: Toxicology III
- Glutathione then rapidly depleted. How does Unconjugated NAPQI act?
- Effects of unconjugated NAPQI
- highly reactive nucleophilic binds with cellular macromolecules / mitochondria
- Precipitous loss of function primarily leads to necrotic hepatic cell death
- Can also lead to renal failure
- Paediatric and elderly patients also at risk increase
- In UK most common cause of hepatic failure (Non- self harm)
- Precipitous loss of function primarily leads to necrotic hepatic cell death
Paracetamol: Toxicology IV
- Treatment for overdose must be given? & guided by ?
- When do we see hepatoxic effects?
- Treatment?
+ If seen within 0-4hrs - Activated charcoal orally reduce uptake by 50-90%
+ 0-36 hrs - Start N-Acetylcysteine iv (see e-BNF)
• Methionine by mouth if NAC cannot be given promptly
- as soon as possible & blood levels of drug
- peak 72 - 96 hrs post ingestion
3.
- Appreciate the general mechanisms underlying autoimmune disease particularly Rheumatoid Arthritis (RA)
- Understand the overarching treatment strategy for managing patients with autoimmune inflammatory conditions (such as RA and lupus).
- Understand the mechanism of action of systemic corticosteroids
- Know the common ADRs of systemic corticosteroids
• Be able to describe the salient features of pharmacological mechanism of
action, pharmacokinetics, ADRs and clinical monitoring (where appropriate) of:
- Azathioprine
- Calcineurin inhibitors (ciclosporin and tacrolimus)
- Mycophenolate mofetil
- Cyclophosphamide
- Methotrexate
- Sulphalazine
- Be aware of the newer ‘biologicals’ and their range of indications
- Understand the action of drugs that block TNF α
