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Clinical Pharmacology, Therapeutics & Principles of Prescribing > Session 8 > Flashcards

Session 8 Flashcards

1
Q
  • 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.
A
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2
Q

Non Steroidal Anti-Inflammatory Drugs (NSAIDs):

  1. Principle action - ?
  2. Three primary therapeutic effects:
A
  1. key enzymes in prostaglandin synthesis
  2. Analgesia

Anti-Inflammatory

Antipyretic

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3
Q

The Inflammatory Response

  1. Fundamental response of body to injurious stimuli - includes wide variety of noxious agents. Give examples:
  2. Why have it?
A
  1. 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
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4
Q

Autacoids Signal the Inflammatory Response

  1. Diverse range of local molecular mediators and signalling agents employed - the Autacoids * including?
  2. Signalling overlap ensures robust inflammatory response
  3. Key feature of autacoids is?
A
  1. Bradykinins
    - Histamine
    - Cytokines
    - Leukotrienes
    - Nitric Oxide
    - Neuropeptides
    - Eicosanoids – Includes Prostaglandins

2.

  1. localised release + short half lives allows fine control of the signalling response
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5
Q

Recognise the central role of arachidonic acid in prostanoid synthesis LO

  1. What is the structure of Eicosanoids and their use?
  2. Variation in synthetic routes give rise to different classes of Eicosanoids: \
  3. All Eicosanoid classes derived from?
A
    • 20 C phospholipid derivatives
      - signalling molecules
    • Prostanoids: Prostaglandins (PGs) Prostacyclins Thromboxanes
      - Leukotrienes
  3. Arachidonic Acid which is cleaved from cell membrane phospholipids
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6
Q

Recognise the central role of arachidonic acid in prostanoid synthesis LO

Draw a diagram showing the synthesise of PGs

A
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7
Q

How is COX-1 Isoform expressed?

  1. COX-1 expressed in ?
  2. PG synthesis by COX -1 has major cytoprotective role of?
  3. What is the t1/2 for PG ?
  4. Due to its constitutive expression, most ADRs caused by NSAIDs effects are due to ?
A

Constitutively Expressed

  1. wide range of tissue types
    • Gastric mucosa

+Myocardium

+ Renal parenchyma - Ensures optimised local perfusion – reduces ischemia

  1. short = 10 mins - need constant synthesis
  2. COX-1 inhibition
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8
Q
  1. How is COX-2 Isoform expressed?
  2. COX-2 expression induced by?
  3. COX-2 appears to be constitutively expressed in parts of the ?
  4. Main therapeutic effects of NSAIDs occur via ?
  5. COX-1 and 2 do not work independently and PG synthesis with both enzymes depends on tissue and organ type
A
  1. Induced by Injurious Stimuli
  2. inflammatory mediators such as Bradykinin
  3. brain and kidney
  4. COX-2 inhibition

5.

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9
Q

Differences in COX-1 and COX-2 tunnel for catalysing Arachidonic Acid

???

A
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10
Q

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

A

1 - first time you have sex ur tight

2 time u r baggy

aspirin is small! Can fit into both

aspirin for ALL

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11
Q

Prostaglandins: General Pharmacology

  1. Prostaglandins bind with ?
  2. Specific actions depends on ?
  3. For PG ‘E’ at least four main types: ?
  4. Often action includes?
A
  1. GPCRs
  2. PG receptor types
  3. EP 1-4
  4. synergising effects of other autacoids – eg. Bradykinin/Histamine
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12
Q

Prostaglandin Pharmacology - Inflammatory Response Mediators

  1. Range of autacoids and prostanoids released post injury esp. ?
  2. Released from ?
  3. Autacoid release also induces ?
  4. Synergise with other autacoids – e.g.
  5. Action of PGs?
A
  1. PGE2 - also PGD2
  2. local tissues and blood vessels
  3. expression of COX-2
  4. Bradykinin/Histamine
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13
Q

Prostaglandin release following injury.

  1. Function of EP2 receptor?
  2. Function of EP1 receptor?
A
  1. Gs -> vasodilation
  2. Gq -> peripheral nociception

2 veSSels

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14
Q

Prostaglandin Pharmacology- Pain 1: Sensitising Afferent Nociception - EP1

How do EP1 receptors sensitise harmful stimuli?

A
  • 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
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15
Q

Pain 1: Sensitising Peripheral Nociception - EP1

  1. GPCR activation results in:
  2. PGs may also activate ?
A
    • Increased neuronal sensitivity to Bradykinin
      - Inhibition of K+ channels
      - Increased Na+ channels sensitivity
      - In combination - these act to increase ‘C’ fibre activity
  2. previously silent ‘C’ fibres
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16
Q

Peripheral Sensitisation (at synapse?)

  1. What effect does EP 1 binding have on C fibres?
  2. What type of receptor is EP1? What does binding to the receptor result in?
A
  1. INCRESE ‘C’ fibre activity
  2. Gq GPCR

INCREASE intracellular Ca2+

Increase Neurotransmitter release

Other autacoids involved INCREASE sensitivity

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17
Q
  1. Explain what this graph is showing
  2. What is the meaning of:

Allodynia

Hyperalgesia

A
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18
Q

Explain how we Pain Sensitise Central Nociception

A
  • 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
19
Q
  1. What are the effects of PGE2 when it binds to EP2 receptor ?
  2. Leading to what overall effect?
A
    • Increase cAMP increase PKA
      - Decrease Glycine Receptor Binding Affinity
      - Increase Pain perception
  2. Increased pain perception
    Sensitisation in dorsal horn by PGE2
20
Q

How do prostaglandins result in pyrexia?

A

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

21
Q

NSAIDs: Therapeutic Effects - General

1 Main therapeutic effects achieved via ?

  1. Pharmacological action for nearly all NSAIDs via ?
  2. Occupation of COX-1 / 2 hydrophobic channel by NSAID competes with ?
  3. With = 50 different NSAIDs wide variation in ?
A
  1. COX-2 inhibition
  2. competitive inhibition of COX-1 and COX-2
  3. AA site occupation
  4. Affinity, Efficacy and COX-1/COX-2 selectivity (see later)
22
Q

NSAIDs: Therapeutic Effects General

  1. Main therapeutic effects achieved via?
  2. Nearly all have therapeutic efficacy as?

Often dominant disease state and individual patient response determine physician choice

A
  1. COX-2 inhibition
  2. analgesics, anti- inflammatories, and antipyretics
23
Q

NSAIDs :Therapeutic Effects Pharmacokinetics

  1. Administration?
  2. Linear pharmacokinetics within therapeutic dose range (see Aspirin/Paracetamol)
  3. T1/2s two groups: ?
  4. Free or bound drug?
A
  1. Typically given orally but many topical preparations for soft tissue injury

2.

  1. T ½ < 6hrs

T ½ > 10 hrs

  1. Many heavily bound to plasma protein 90-99%
24
Q

Appreciate the use of NSAID as analgesics, anti-inflammatories and antipyretics LO

NSAIDs : Main Therapeutic Uses

  1. When is NSAIDS used as Anti-Inflammatories?

Analgesia

  1. What type of pain is it used for? Why is it better than other pain relief?
  2. When used?
A
  1. Very wide use in Musculoskeletal Disorders – Rheumatoid/Osteoarthritis
  2. 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
25
Q

Describe the major ADRs / drug interactions associated with NSAIDs LO

NSAIDs: ADRs

  1. What mechanism of action of NSAIDS result in ADRS?
  2. Long term use in elderly - particularly associated with?
  3. Major ADRs seen in ?
  4. Renal ADRs occur in compromised individuals with ?
A
  1. Inhibition of COX-1 constitutive PG synthesis
  2. iatrogenic morbidity and mortality
  3. stomach /GI tract
  4. HRH or hypovolaemia
    - Heart failure
    - Renal disease
    - Hepatic cirrhosis
26
Q

NSAIDs: GI ADRs

  1. GI ADRs in = ?
  2. Specifically what are the GI ADRs?
  3. Gastric COX-1 PGE secretion throughout GI tract, stimulates ?
  4. NSAIDs especially long term - have high incidence of GI ADRs between 10-30%
  5. Offset GI ADRs (long term) with PPIs or misoprostol 2
A
  1. 35% users. Often asymptomatic
  2. varying degrees stomach pain, nausea, heartburn, gastric bleeding, ulceration
  3. cytoprotective mucus secretion throughout GI reduce acid secretion and promote mucosal blood flow

4.

27
Q

NSAIDs: Renal/Renovascular ADRs

  1. Renal ADRs - in HRH compromised (esp neonates/elderly) fgdue to renal perfusion blood flow DECREASED
  2. PGE2 & PGI2 maintain renal blood flow
  3. If reduced by NSAIDs then GFR DECREASED - further risk of renal compromise - dose and use dependent risk INCREASE
  4. Na+/K+/Cl- and H2O retention follow with increased likelihood of hypertension
A

1.

2.

3.

4.

28
Q

NSAIDs: Other ADRs

  1. Vascular ADRs?
  2. Hypersensitivity ADRS?
  3. What syndrome can this result in? Describe this syndrome?
A
  1. Risk INCREASE bleeding time INCREASE bruising haemorrhage
  2. • Skin rashes (15% for some NSAIDs) usually mild

Rare but very serious - Stevens Johnson syndrome*

• Bronchial asthma - Rx care in asthmatics (10% incidence)

  1. 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

29
Q

What is this image showing?

A

Stevens Johnson Syndrome - Severe examples

Immune-complex-mediated hypersensitivity disorder

Compromised hepatic function

Rash - skin mucous membranes

30
Q

NSAIDs – Specific COX-2 Inhibitors

  1. Large research effort put into developing highly selective COX-2 inhibitors e.g. ?
  2. Theoretically overcome ADRs due to COX-1 inhibition with equal efficacy to standard NSAIDs
  3. Explain the ADRs for specific COX-2 inhibitors
A
  1. Rofecoxib, celecoxib,

2.

  1. 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

31
Q

NSAIDs: Drug Interactions Therapeutic Pharmacodynamic

  1. Why do we use NSAIDS in combination with low dose opiates?
  2. What different mechanisms do NSAIDS + opiates act to extend range?
  3. What does combined NSAIDS and opiates do to ADRs Reduces ADRs seen with opiates alone.
A
  1. extends therapeutic range for treating pain
  2. see Opiate Lecture
32
Q

NSAIDS in Combination

  1. How do NSAIDs given in combination effect ADRs?
  2. NSAIDs together can affect each others PK/PDs due to ?
  3. What happens when we give NSAIDs + low dose Aspirin
A
  1. increase risk of ADRs - often occurs due to self medication with NSAIDs
  2. competition for plasma protein binding sites - many NSAIDs heavily bound - up to 90-99%
  3. Compete for COX-1 binding sites - may interfere with cardioprotective action of Aspirin
33
Q

NSAIDs: Drug Interactions NSAID protein binding can affect PK/PDs

  1. Highly protein bound drugs affected by NSAIDs include: (3)
  2. 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?
A
    • Sulphonylurea

+ Warfarin

+ Methotrexate

    • Sulphonylurea - Hypoglycaemia

+ Warfarin – Increased Bleeding

+ Methotrexate – Wide ranging serious ADRs

34
Q

• 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

  1. What is the effect of aspirin on COX enzymes?
  2. Unique PK profile. What is its half life?
  3. Salicylate PKs dose dependent. What is its half life?
  4. Aspirin use?
A
  1. Only NSAID to irreversibly inhibit COX enzymes by acetylation
  2. T½ less than 30 minutes rapidly hydrolysed in plasma to salicylate
  3. At lower doses first order t½ ≈ 4hrs

At higher doses ≈ 12x300 mg tablets/day zero order kinetics apply

  1. cardioprotective (75 mg)

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

35
Q

Give an example of a unique non NSAID Non-Opiate Analgesic

A

Paracetamol

36
Q

Paracetamol: A Unique Non NSAID Non-Opiate Analgesic

  1. Paracetamol is a unique ‘non NSAID’, why?
  2. Very effective for?
  3. At therapeutic doses has much better ADR profile than other NSAIDs
  4. Use?
  5. Therapeutic doses:
A
  1. no anti-inflammatory action - more of a NOAD
  2. mild/moderate analgesia & fever

3.

  1. moderate pain and fever
  2. 8 x 500 mg tablets/day
37
Q

Paracetamol: Pharmacology

  1. Mechanism?
  2. PKs first order in healthy patient t½ ≈
A
    • 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 ??
  2. 2-4 hrs

• Caution ! in those with compromised hepatic function or alcoholics

38
Q

Paracetamol:Toxicology 1

  1. Normal doses - Linear PKs
  2. How is it metabolised?
  3. What is NAPQI? How is it metabolised?
A

1.

  1. Mainly use Phase II Conjugation – (Glucoronide 60% & Sulphate 30%)

Some Phase 1 Oxidation – NAPQI *10%

  1. 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 !

39
Q

Paracetamol: Toxicology II

  1. What dose of paracetamol is fatal?
  2. At high doses Paracetamol PKs become?
  3. What happens to the metabolism of parecetomal to go from in the therapeutic window to toxic?
A
  1. Single doses > 10 g (20 tablets) potentially fatal!
  2. 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
40
Q

NAPQI

NAPQI has spare electron groups on the = O atoms and =N- atoms !

Clinical significance?

A

Loves positive charges and will react !

41
Q

Paracetamol: Toxicology III

  1. Glutathione then rapidly depleted. How does Unconjugated NAPQI act?
  2. Effects of unconjugated NAPQI
A
  1. 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)
42
Q

Paracetamol: Toxicology IV

  1. Treatment for overdose must be given? & guided by ?
  2. When do we see hepatoxic effects?
  3. 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

A
  1. as soon as possible & blood levels of drug
  2. peak 72 - 96 hrs post ingestion

3.

43
Q
  • 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

Clinical Pharmacology, Therapeutics & Principles of Prescribing (19 decks)

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