VIVA: Pharmacology - Analgesics and anti-inflammatories

Question 1

Describe the pharmacokinetics of ibuprofen

Answer 1

2 needed to pass:
- NSAIDs well-absorbed, food does not substantially change their bioavailability
- Highly protein bound
- Highly metabolised by liver (cytochrome p450)

Question 2

Describe the pharmacodynamics of ibuprofen

Answer 2

Inhibition of prostaglandin synthesis*
Additional possible mechanisms of action, including inhibition of chemotaxis, downregulation of IL-1 production, decreased production of free radicals and superoxide, and interference with calcium-mediated intracellular events
NSAIDs are reversible inhibitors of COX*
Anti-inflammatory, antipyretic and analgesic*

• needed to pass

Question 3

What are the side effects of NSAIDs?

Answer 3

CNS: headaches, tinnitus, dizziness
CVS: fluid retention, HTN, oedema, rarely MI, CCF
GIT *: abdominal pain, dyspepsia, nausea, vomiting, ulcers or bleeding
Renal *: renal insufficiency, renal failure, hyperkalaemia, proteinuria
Haematologic: rarely thrombocytopaenia, neutropenia, aplastic anaemia
Hepatic: abnormal LFTs, rarely liver failure
Pulmonary: asthma
Skin: rashes (all types), pruritis

*4 side effects needed to pass (must include GIT and renal)

Question 4

Describe the mechanism of action of fentanyl

Answer 4

Synthetic opioid that acts on the mu receptor*

*needed to pass

Question 5

Describe the pharmacokinetics of fentanyl

Answer 5

• High first-pass metabolism *, low oral bioavailability
• Highly lipid soluble
• Duration of action 1-2hr *
• Half-life 5mins
• Metabolised by P450 CYP 3A4 with no active metabolites
• Transdermal, mucosal and IM absorption are good
• Fentanyl may be given IV, IM, IN, SC, SL/buccal (with lozenge), transdermal patch, epidural

*needed to pass + two routes

Question 6

Describe the potency of fentanyl relative to morphine

Answer 6

100x more potent (0.1mg of fentanyl = 10mg morphine)

Question 7

List the adverse effects of fentanyl

Answer 7

4 needed to pass:
- Respiratory depression
- Nausea and vomiting
- Dysphoria
- Cough
- Sedation
- Constipation
- Urinary retention
- Itch
- Urticaria
- Chest wall and laryngeal rigidity

Question 8

Describe the pharmacokinetics of oxycodone

Answer 8

Absorption:
- Commonly given orally *, also available subcut, IV and IM as well as PR and epidural
- Good oral absorption *
- Low first pass metabolism (cf morphine)

Distribution:
- High volume of distribution

Metabolism:
- Duration of action 3-4hrs, longer if controlled release formulation *
- Hepatic metabolism by P450

Elimination:
- Metabolites excreted by kidneys

Dosing:
- Relative potency: 10mg morphine = 4.5mg oxycodone

*needed to pass + one characteristic

Question 9

What strategies may be used when prescribing oxycodone to reduce the development of dependence?

Answer 9

3/5 to pass:
- Establish goals at start of Rx
- Smaller doses at longer intervals
- Limit doses
- Use of controlled release preparations
- Combine with non-opioid analgesics
- Frequent evaluation of ongoing requirements

Question 10

What is the mechanism of action of morphine?

Answer 10

• Acts on receptors: mu */delta/kappa
• Reduce presynaptic neurotransmission (especially glutamate) *
• Inhibit postsynaptic neurons *
• Central (thalamic action)

*Mu receptors + one other mechanism to pass

Question 11

Why do opiates cause respiratory depression?

Answer 11

Inhibition of brainstem respiratory controls *, allowing less response to hypercapnoea

*needed to pass

Question 12

How is morphine metabolised?

Answer 12

Conjugated in liver* (morphine-3-glucuronide = most)
Small amount (10%; morphine-6-glucuronide = increased analgesic potency)
Renal excretion

*needed to pass

Question 13

How does oxycodone produce its analgesic effects?

Answer 13

Opioid agonist that acts mainly on mu receptors* in brain and spinal cord, but also outside CNS

*needed to pass

Question 14

Outline the mechanisms of action for aspirin

Answer 14

Irreversible non-selective cyclooxygenase inhibition* (COX-1 and COX-2) resulting in:
- In platelets: irreversible inhibition of COX-1 results in reduction in thromboxane A2 and inhibition of platelet aggregation* for the life of the platelet (10 days)
- In tissues: inhibits prostaglandin synthesis* (COX-2), results in anti-inflammatory action as well as analgesic and antipyretic effects

*needed to pass: also need to mention platelet effect (COX-1) AND tissue (COX-2) anti-inflammatory or analgesic effect

Question 15

Describe the pharmacokinetics of aspirin

Answer 15

Absorption:
- pKa 3.5, rapidly absorbed from stomach and intestine* as acetylsalicylic acid
- Peak plasma levels within 1-2hrs
- ASA rapidly hydrolysed to salicylic acid by esterases in plasma and blood with half-life of 15mins

Distribution:
- Salicylate bound to albumin
- Small Vd

Metabolism:
- Saturable metabolism with increasing doses (switches from first to zero order metabolism)*

Elimination:
- Urinary alkalinisation increases excretion of salicylate and its conjugates*

*needed to pass

Question 16

What are the adverse effects of therapeutic doses of aspirin?

Answer 16

CNS: headache, tinnitus, dizziness
CVS: fluid retention, HTN, oedema
GIT: abdo pain, nausea and vomiting, ulcers, bleeding*
Haem: thrombocytopaenia, neutropaenia, aplastic anaemia
Hepatic: abnormal LFTs, liver failure
Pulmonary: asthma*
Skin: all types of rashes, pruritis
Renal: impairment and failure, hyperkalaemia, proteinuria
Allergy*

• needed to pass

Question 17

Describe what happens to aspirin in the gut following oral administration

Answer 17

Highly soluble in acid environment of the stomach as it is a weak acid (rapidly absorbed)
Becomes much less soluble (100x less) in the alkali environment of the upper small bowel
Most of the administered dose is absorbed in the small bowel (due to the vastly increased surface area)
Possibility of formation of concretions/bezoars

Question 18

What are the toxic effects of aspirin in overdose?

Answer 18

Salicylism (5 needed to pass):
- Vomiting, tinnitus, vertigo, loss of hearing
- Tachypnoea (leading to respiratory alkalosis)
- Fever
- Dehydration
- Metabolic acidosis
- Hyperglycaemia
- Clotting disturbance
- CVS collapse
- Renal and respiratory failure
- Coma

Question 19

What are the therapeutic indications of asthma?

Answer 19

TIA
ACS
Pre-thrombolysis
Anti-inflammatory
Analgesia
Anti-pyretic

Question 20

Describe the mechanism of action of colchicine

Answer 20

Anti-inflammatory effect* (binds to tubulin, inhibits WBC migration and phagocytosis)
Inhibits formation of leukotriene B4
No effect on uric acid metabolism*

• needed to pass

Question 21

What are the indications and dosage of colchicine?

Answer 21

Treatment of acute episodes of gout (0.6-1.2mg PO 12hrly until pain reduces or diarrhoea results; 8mg is a fatal dose)*
Gout prophylaxis (0.6mg PO TDS)*
Prevention of Mediterranean fever
Treatment of sarcoid arthritis

• need either of these to pass

Question 22

Describe the mechanism of action of the COX-2 selective inhibitors

Answer 22

Inhibits prostacyclin synthesis by selectively binding to and blocking the active site of the COX-2 isoenzyme

Question 23

What adverse effects can be associated with the use of COX-2 selective inhibitors?

Answer 23

2/3 needed to pass:
- Renal toxicity
- GIT (fewer than non-selective NSAIDs)
Possible increased CVS thrombotic events

Question 24

What other drugs are inhibitors of the cyclooxygenase enzyme system?

Answer 24

Arthritis
Non-steroidals

Question 25

What is drug potency?

Answer 25

Dose or concentration to achieve 50% maximal effect (EC50 or ED50)

Question 26

Draw and explain dose-response curves comparing morphine with fentanyl

Answer 26

Question 27

What is bioavailability?

Answer 27

Fraction of unchanged drug reaching the systemic circulation* following administration by any route

• needed to pass

Question 28

What factors affect bioavailability?

Answer 28

1. Extent of absorption*
   - Too hydrophilic or too lipophilic = decreased absorption
   - Reverse transporter associated with p-glycoprotein pumps drug back to gut lumen = decreased absorption
   - Gut wall metabolism = decreased absorption
2. First pass metabolism*
   - Metabolism by liver before it reaches systemic circulation
   - Small additional effect if drug has biliary excretion
3. Rate of absorption
   - Determined by site of administration and drug formulation

• needed to pass (with reasonable explanation of each)

Question 29

What is the bioavailability of ibuprofen?

Answer 29

High:
- Weak organic acid
- Well-absorbed rapidly
- Minimal first pass metabolism*

• needed to pass

Question 30

Describe the central nervous effects of morphine

Answer 30

Analgesia*
Sedation*
Respiratory depression* (dose-related): inhibits brainstem respiratory mechanisms, limited response to hypercarbia
Euphoria
Cough suppression
Miosis
Truncal rigidity
Nausea and vomiting
Temperature

• should be able to describe in detail

Question 31

Describe the peripheral effects of morphine

Answer 31

Cardiovascular: peripheral arterial and venous dilation via histamine release and central depression of vasomotor stabilising mechanisms
GI: constipation
Biliary: smooth muscle constriction may cause biliary colic
Renal: decreased renal function due to decreased renal plasma flow; antidiuretic effect of mu opioids
Uterus: may prolong labour
Genitourinary: increased ureteral and bladder tone may lead to urinary retention
Neuroendocrine: stimulates ADH, prolactin and GH release, inhibits LH
Pruritis: CNS effect and peripheral histamine release
Immune: effects on lymphocyte proliferation, antibody production and chemotaxis

• should be able to describe in detail

Question 32

Describe the effects of morphine on the different opioid receptors

Answer 32

Full agonist at the mu receptor*:
- Analgesia, sedation, respiratory depression, decreased GI transit, modulation of hormone and neurotransmitter release

Minor activity at delta receptor:
- Analgesia, modulation of hormone and neurotransmitter release

Minor activity at kappa receptor:
- Analgesia, psychomimetic effects, decreased GI transit

• needed to pass + one other receptor

Question 33

What is the mechanism of action of morphine at the cellular level?

Answer 33

By binding to specific G-protein-coupled receptors in brain and spinal cord:
- Closes voltage-gated Ca2+ channels: decreased Ca2+ influx on presynaptic nerve terminals and decreased transmitter release
- Hyperpolarises postsynaptic neurons by increasing K+ conductance, producing an inhibitory postsynaptic potential

Question 34

How does aspirin differ from other NSAIDs in its action on COX?

Answer 34

Cyclooxygenase is the key catalyst for arachidonic acid conversion to prostaglandins
NSAIDs inhibit COX, thus inhibiting conversion
Aspirin (original NSAID) irreversibly inhibits COX, whilst the newer NSAIDs (ibuprofen, diclofenac) reversibly inhibit COX*

Two types of COX exist:
- COX-1 is expressed in most cells
- COX-2 is inducible and its expression varies depending on stimulus

Selective COX-2 inhibitors (celecoxib) do not affect platelet function at usual doses, whilst the other NSAIDs do inhibit platelet aggregation

• needed to pass

Question 35

Name some drugs that are used in the treatment of opiate addiction

Answer 35

Methadone*
N-acetylmethadol
Buprenorphine
Clonidine
Lofexidine
Naltrexone
Naloxone

• needed to pass + one other

Question 36

Outline the principles of how drugs used to treat opioid addiction work

Answer 36

Overall agents must be orally active and long-acting*

Methadone*:
- Long-acting opioid antagonist
- Orally active
- Patient can be stabilised and gradually withdrawn
- Also addictive

N-acetylmethadol:
- Even longer-acting methadone analogue

Buprenorphine:
- Partial opioid agonist that can be given once daily
- Low doses for detoxification, higher doses for maintenance

Clonidine:
- Centrally-acting sympatholytic agent that mitigates signs of withdrawal (sympathetic overactivity)

Lofexidine:
- Clonidine analogue with less hypotensive effects

Naltrexone:
- Long-acting orally active pure opioid antagonist
- Patients must be detoxified first

Naloxone:
- Rapid onset pure antagonist
- Short half-life
- Precipitates withdrawal

• needed to pass + pharmacodynamics of one other agent

Question 37

Describe the clinically important pharmacological differences between morphine and fentanyl

Answer 37

Morphine is naturally occurring, fentanyl is synthetic

2/3 needed to pass:
- Receptor effects: both are strong agonists (all receptors), potency of fentanyl exceeds morphine
- Absorption: both morphine and fentanyl have low oral:parenteral potency ratios
- Elimination: elimination half-life of morphine exceeds fentanyl

Question 38

How does methadone differ from morphine and fentanyl?

Answer 38

Pharmacodynamic differences:
- Methadone also blocks NMDA receptors and monoamine reuptake (may explain its ability to relieve difficult-to-treat pain)

Pharmacokinetic differences:
- Methadone has a high oral:parenteral potency ratio*
- Elimination half-life of methadone&raquo_space; morphine > fentanyl*
- Methadone has highly variable pharmacokinetics between individuals

• needed to pass

Question 39

What advantages and disadvantages might a drug like buprenorphine have in the treatment of heroin addiction, as compared to methadone?

Answer 39

1. Buprenorphine is a partial agonist at the mu receptor, and has a long duration of action due to slow dissociation from the receptor; said to be as effective as methadone in the detoxification and maintenance treatment of heroin addiction
2. Lower risk of overdose fatalities compared to methadone due to its partial agonist action
3. Slower receptor dissociation renders its effect resistant to naloxone reversal and prevents action of other narcotic analgesics (if needed)

• must describe what buprenorphine does and that it is relatively safe to pass

Question 40

What adverse effects of oxycodone might you anticipate?

Answer 40

3 needed to pass:
- Sedation
- Respiratory depression
- Nausea and vomiting
- Hypotension
- Dysphoria
- Biliary colic
- Pruritis
- Use with caution in renal failure (accumulation of active metabolites)

Question 41

Describe the pharmacokinetics of paracetamol

Answer 41

3 needed to pass:
- Rapid absorption
- Oral bioavailability 70-90%
- Peak concentration after 30-60mins
- Half-life 2-3hrs
- Slightly protein bound, Vd 1L/kg (approximates body weight)
- Hepatic metabolism: 95% undergoes glucuronidation and sulfation, 5% undergoes metabolism via CYP 450 enzymes (phase 1 hydroxylation reaction) to form toxic NAPQI, which is usually detoxified by glutathione*
- Renal excretion (<5% unchanged)
- First order kinetics

Question 42

Describe the mechanism by which paracetamol causes toxicity

Answer 42

Zero order kinetics*
Paracetamol is conjugated with glucuronide and sulphate (by transferase enzymes): this pathway becomes saturated in overdose, allowing increasing paracetamol to be metabolised by the smaller CYP 2E1 pathway to NAPQI (N-acetyl-p-benzoquinone imine)
NAPQI is detoxified by glutathione which becomes depleted resulting in high levels of toxic metabolite (NAPQI)*

• needed to pass

Question 43

How does N-acetylcysteine work in the treatment of paracetamol overdose?

Answer 43

Sulfhydryl group donor - restores hepatic reduced glutathione levels
Or acts as alternative substrate for conjugation with the toxic metabolite

• need concept to pass

Question 44

What is the toxic dose of paracetamol?

Answer 44

150-200mg/kg or >7g in an adult

(>4g/day can cause LFT derangement; >150mg/L 4hrs post ingestion indicates risk of liver injury)

Question 45

What is the mechanism of action of paracetamol?

Answer 45

Weak COX-1 and COX-2 inhibitor in peripheral tissues (preferentially inhibits COX-2*)

• needed to pass

Question 46

What are the clinical manifestations of paracetamol toxicity?

Answer 46

4 needed to pass:
- Nausea and vomiting
- Abdominal pain
- Liver failure
- Renal failure (tubular necrosis)
- HAGMA
- Coma with massive doses

Question 47

Describe the enhanced elimination strategies employed in managing a patient with salicylate overdose

Answer 47

pH manipulation/urinary alkalinisation
Forced diuresis
Dialysis (peritoneal, haemodialysis, haemofiltration, haemoperfusion)