IC13 Pharmacology of Analgesics

Question 1

What are the general targets of NSAIDs, Opioids and paracetamol?

Answer 1

1. NSAIDs – block acute inflammatory response at site of injury
2. Opioids – blocks the transmission of pain through nerves specifically at the spinothalamic pathway
3. Paracetmol – modulate how brain interprete signals

Question 2

What happens to the phospholipids in the cell membrane when the phospholipase A2 acts on it?

Answer 2

Phospholipase A2 converts cell membrane phospholipids to arachidonic acid (AA)
AA is converted to

• lipoxins (by 15-lipoxygenase),
• prostanoids (by cyclooxygenase)  acute inflammation
• leukotrienes (by 5-lipoxygenase)  chronic inflammation and immune responses

Question 3

What are the diff types of prostanoids?

Answer 3

Types of Prostanoids:

1. Prostacyclins (PGI2)
2. Prostaglandins (PGE2)
3. Thromboxanes (TXA2)
   Different types of Prostanoids in different types of tissues

Question 4

What are the effects of the diff prostanoids?

Answer 4

Effects PGI2 PGE2 TXA2
Vasodilation / constriction dilate dilate Constrict
Inhibit / promote platelet aggregation inhibit NIL promote
Vascular Permeability NIL increase NIL
Pain NIL pain NIL

Question 5

What are the 4 Aspirin pharmacological actions?

Answer 5

1. anti-inflammatory
2. analgesia
3. anti-platelet
4. anti-pyretic

Question 6

What is the patho for aspirin anti-inflammatory action?

Answer 6

1. Anti-inflammatory
   a. Blocks COX at site of injury → ↓PGI2 & PGE2
   b. ↓vasodilation, vascular permeability & pain

Question 7

What is the patho for aspirin analgesia action?

Answer 7

2. Analgesic
   a. Blocks COX at site of injury → ↓ PGE2 which sensitizes the nociceptive fibers to stimulation by other inflammatory mediators
   b. Additional analgesic actions in CNS
   c. Analgesic ceiling → NSAIDs block sensitization only and does NOT block nociceptors directly → thus only for mild-moderate pain
   i. Bradykinin and leukotriene are the inflammatory mediators that activates the nociceptors, while PGE2 sensitizes the nociceptor (meaning ↑extent of pain) → ↓ PGE2 does not mean bradykinin and leukotriene are not there & in severe pain, there are excess of bradykinin and leukotriene that NSAIDs do not block

Question 8

What is the patho for aspirin anti-pyretic action?

Answer 8

3. Anti-pyretic
   a. Block COX in hypothalamus → ↓ PGE2 → ↓ restarting the body’s thermostat → ↓ fever
   b. NSAIDs do NOT alter normal body temperature

Question 9

What is the patho for aspirin anti-platelet action?

Answer 9

4. Anti-platelet
   a. Irreversible COX-1 inhibitor (platelet no nucleus) → Block COX-1 in platelet → ↓TXA2 irreversibly → ↓platelet aggregation (1-2wks)
   b. Reversible COX-2inhibitor (endothelial cells have nucleus) → Block COX-2 in endothelial cells → ↓PGI2 → slight ↑platelet aggregation (a few hrs)

• Not used as painkiller due to many ADRs, overtaken by paracetamol

Question 10

What is the ADRs of Aspirin?

Answer 10

1. Reye’s syndrome
   a. Children recovering from viral infections and taking aspiring have a higher risk of getting Reye’s syndrome
   b. Rare but life threatening, swelling of brain and liver, vomiting, personality changes, listlessness, delirium, convulsions, loss of consciousness
   c. Avoid in children
2. See the rest under ADRs of NSAIDs

Question 11

Why do you have to avoid aspirin in children?

Answer 11

Reye’s syndrome

Question 12

How would you choose naproxen, indomethacin and diclofenac? (can just open)

Answer 12

Choice of NSAIDs:

1. Naproxen
   a. More effective in women since ↑free fraction
   b. BD dosing
   c. Often used for dysmenorrhea
2. Indomethacin
   a. Strongly anti-inflammatory since have steroid like phospholipase A inhibition (block all the pathways)
   b. But bad ADRs e.g. confusion, depression, psychosis, hallucinations thus not 1st line
3. Diclofenac
   a. Short t1/2, thus ↓ GI effects
   b. Longer t1/2 in synovial fluids, thus useful for inflammatory joint disease

Question 13

What are the ADRs of NSAIDs?

Answer 13

ADRs of NSAIDs

1. GI ADRs
   a. ADRs: dyspepsia, N&V, anorexia, abdominal pain, ulcers, bleeding risk
2. Renal ADRs
   ii. Hyperkalaemia (PGI2 normally stimulates K+ excretion)
   iii. Peripheral edema
   iv. HTN
3. AKI
4. Pseudo-allergic reaction + Bronchospasm
   a. ADRs: skin rashes, swelling, itching, nasal congestion anaphylactic shock
5. Bleeding

Question 14

What is the explanation for GI ADR effects when using NSAIDs?
What are the RFs?
How to manage this?

Answer 14

1. GI ADRs
   a. ADRs: dyspepsia, N&V, anorexia, abdominal pain, ulcers, bleeding risk
   b. (Protective factors of PGE2) PGE2 ↓gastric acid secretions, ↑mucosal blood flow, ↑mucus secretion, ↑bicarbonate secretions
   c. Explanation: NSAIDs ↓PGE2 → ↓protective factors → GI ADRs
   d. RF: >65y/o, Hx of ulcer, chronic use of NSAIDs, concurrent steroids, anticoagulants, antiplatelets (if >=3 means high risk)
   e. Management:
   i. Don’t’ use >5days
   ii. Avoid non-selective NSAIDs e.g. ibuprofen (but ibuprofen has less GI SE than naproxen)
   iii. Use celecoxib but with caution + PPI

Question 15

What is the explanation for Renal ADR effects when using NSAIDs?
What are the RFs?
How to manage this?
(Not including AKI RF)

Answer 15

2. Renal ADRs (both COX-1 & 2)
   a. Explanation: Inhibition of both PGI2 and PGE2 alters renal blood flow dynamics (glomerular filtration + electrolyte mvt)
   b. Inhibition of PGE2:
   i. Na retention (major) → PGE2 normally inhibit Na reabsorption at TAL
   ii. Water retention
   iii. Peripheral edema
   iv. HTN
   c. Inhibition of PGI2:
   i. Suppression of Renin and aldosterone secretion (RAAS normally will ↑retention, PGI2 normally stimulates Na reabsorption)
   ii. Hyperkalaemia (PGI2 normally stimulates K+ excretion)
   iii. AKI → avoid diuretics, ACEI & ARBs → all ↓kidney functions (triple whammy) → look out for renal panel, BP
   d. %Na reabsorption at TAL (due to PGE2 inhibition) > %Na cleared in tubules at DCT (Inhibition of PGI2) → overall, Na retention
   e. Often seen in long acting NSAIDs e.g. celecoxib, naproxen
   f. Management:
   i. consult Dr
   ii. monitor BP

Question 16

What are the RFs for AKI when using NSAIDs??
How to manage this?

Answer 16

AKI
a. RF for NSAID-induced AKI

1. CKD: eGFR<15 avoid NSAIDs & coxibs
2. ↑age (>65y/o), chronic HTN, atherosclerosis → narrowing renal arterioles which ↓dilation capacity
3. Pre-existing glomerular disease renal insufficiency → ↓dilation capacity thus ↓ ability to maintain GFR
4. Volume depletion (GI/renal salt/water loss, sepsis, blood loss, diuretic use, nephrotic syndrome, cirrhosis, HF (effective vol. depletion))
   → ↓afferent glomerular arteriole pressure & stimulates the secretion of angiotensin II (more pee)
5. Use of ACEi/ARBS → prevent efferent arteriole vasoconstriction thus ↓ ability to maintain GFR
6. Use of triple whammy → diuretics cause volume depletion
7. Aminoglycosides, amphotericin B, radiocontrast material

b. Management:
i. Avoid PO NSAIDs, if really need → use TOP NSAIDs + Monitor SCr, electrolytes

Question 17

What is the explanation for pseudoallergy + bronchospasm effects when using NSAIDs?
What are the RFs?
How to manage this?

Answer 17

4. Pseudo-allergic reaction + Bronchospasm
   a. ADRs: skin rashes, swelling, itching, nasal congestion anaphylactic shock
   b. Explanation: block COX (mainly COX-1) → more AA to be converted to leukotrienes → excess leukotrienes lead to bronchospasm in asthma patients + allergic reaction-like sx
   c. Not a true allergy reaction → all NSAIDs will cause it e.g.aspirin/ibuprofen, thus no point changing to other NSAIDs
   d. Effects stronger for aspirin (irreversible cox inhibitor)
   e. Caution in:
   i. Asthma
   ii. Chronic Urticaria
   iii. Nasal polyps
   f. Management:
   i. Avoid all non-selective NSAIDs e.g. ibuprofen
   ii. Use celecoxib but with caution (best to avoid)

Question 18

What is the explanation for bleeding effects when using NSAIDs?
What are the RFs?
How to manage this?

Answer 18

5. Bleeding
   a. Explanation: failure of hemostasis, bruising
   b. Greater risk for COX-1>COX-2 inhibition
   c. Effects stronger for aspirin (irreversible cox inhibitor)
   d. Decreasing GI risk: ketoprofen >aspirin >naproxen >ibuprofen >diclofenac >celecoxib >etoricoxib
   e. Caution in:
   i. Surgery in people already on NSAIDs
   ii. Antiplatelets, anticoagulants
   f. Management: stop 3 days before surgery (aspirin: 1week)

Question 19

What is the MOA of coxibs?
Why does it have poor anti-pyretic effects?

Answer 19

MOA of COX-2 Selective Inhibitors

• More cox-2 selective inhibition → ↑anti-inflammatory, ↑analgesic
• Poor antipyretic because have huge chemical structures, thus hard to pass the BBB

Question 20

What are the ADRs of coxibs?

Answer 20

Coxib ADRs:

1. Renal ADRs
2. Delayed follicular rupture (caution)
3. Premature closure of ductus arteriosus (fetal lung bypass) in late pregnancy
4. Impaired healing of wounds
5. ↑Thrombosis
6. CV events e.g. Heart attack & stroke
7. GI ADRs

Question 21

What is the explanation for renal effects when using coxibs?

Answer 21

1. Renal ADRs
   a. Explanation: COX-1 and COX-2 are constitutively expressed in kidneys → thus not only NSAIDs but coxibs have renal toxicity + COX-2 produces both PGI2 and PGE2
   b. Often seen in long acting NSAIDs e.g. celecoxib, naproxen

Question 22

Why NSAIDs and coxib have to be CI in 3rd trimester of pregnancy?

Answer 22

3. Premature closure of ductus arteriosus (fetal lung bypass) in late pregnancy
   a. CI in 3rd trimester (all NSAIDs since they block COX-2 too and coxibs)

Question 23

What is the explanation for impairment of healing when using coxibs?
What are the RFs?
How to manage this?

Answer 23

4. Impairment of wound healing
   a. May exacerbate ulcers
   b. Caution in:
   i. Existing ulcers/ulcer risk factors
   ii. Post-surgical analgesia
   iii. Fractures and bone repair
   c. Remove all NSAIDs and coxibs to allow ulcers to heal → then later start coxibs

Question 24

What is the explanation for increase in thrombosis by coxibs?

Answer 24

5. ↑Thrombosis
   a. Explanation: Block COX-2 → more AA available for COX-1 to convert it to TXA2 which ↑platelet aggregation

Question 25

What is the explanation for CV events when using coxibs? What are the RFs? How to manage this?

Answer 25

6. CV events e.g. Heart attack & stroke a. Explanation: **renal toxicity causing HTN + ↑thrombosis → ↑risk of heart attack & stroke** b. Caution in: i. Elderly ii. History of cardio/cerebrovascular disease c. Management of cardiovascular toxicity: i. Avoid diclofenac & COX-2 selective NSAIDs other than celecoxib ii. **Use celecoxib <400mg per day/ibuprofen for <=5days / paracetamol**

Question 26

Why coxibs still can cause GI effects?

Answer 26

7. GI ADRs a. ADRs: acid reflux, nausea b. Celecoxib still have COX-1 inhibition even though it is cox-2 selective, thus still possible to have GI ADRs c. Dose-dependent

Question 27

What are the CI of NSAIDs?(8)

Answer 27

CI for NSAIDs: 1. Severe kidney impairment (eGFR<30) 2. Severe heart failure, uncontrolled HTN, peripheral arterial disease, IHD → but can consider celecoxib 200mg/day 3. Active GIT ulcer/bleed/Bleeding disorder 4. Use of systemic corticosteroids (↑GI ulcers or bleeds)/antiplatelets/anticoagulants 5. Multiple RF for NSAIDs toxicity 6. 3rd trimester of pregnancy (24-40wks) 7. Asthma/COPD 8. Hypersensitivity 9. Extra counselling: do not take with food as can affect absorption

Question 28

What is the MOA of paracetamol? What is the usual dose? What is max dose? When should you refer to the A&E? Who to be caution in?

Answer 28

MOA of Paracetamol - CNS-selective COX inhibition - Analgesia, Antipyretic - NOT anti-inflammatory - Mild-moderate pain - Dosing: 500mg-1g q4-6hrs daily PRN o Most reach analgesic ceiling at 500mg - Max dose: 4g/24hrs o If >10g/24hrs → A&E IMMEDIATELY due to high risk of heptatotoxicity - Caution in: o Hepatic dysfunction o alcohol abuse - Dose reduction in underweight, liver disease, frail

Question 29

What are the advantages of paracetamol?

Answer 29

Advantages of paracetamol: 1. Good analgesic 2. Potent anti-pyretic 3. No GIT ADRs other than the usual ones 4. Few ADRs 5. Few DDI

Question 30

What are the limitations of paracetamol? What to give when on paracetamol overdose? What to avoid when taking paracetamol?

Answer 30

Limitations of Paracetamol: 1. Weak anti-inflammatory 2. Toxic dose cause N&V, liver damage, allergic skin reactions 3. Hepatotoxicity occurs when overdose/chronic alcohol use a. CYP2E1 converts paracetamol into toxic metabolite → toxic metabolite + glutathione → non-toxic metabolite b. Alcohol induces CYP2E1 + depletes glutathione + paracetamol overdose → hepatotoxicity c. Management: **give IV N-acetyl-cysteine (will replenish glutathione)**, avoid alcohol

Question 31

How should you use paracetamol and NSAIDs if you want to use combination?

Answer 31

Paracetamol + NSAIDs combination Use paracetamol & NSAIDs together at the same time → synergistic effect, stronger and longer analgesia

Question 32

What is the MOA of opioids? What is its place in therapy for pain? How to use if want to use it?

Answer 32

- Analgesia - NOT anti-inflammatory - Severe pain - NOT 1st line - Use at lowest dose of the weakest effective opioid, shortest duration

Question 33

What are the weak and strong opioids?

Answer 33

Weak opioids: - Tramadol (Max single dose = 100mg) o Additional NE and 5-HT reuptake inhibition - Codeine (Max single dose = 60mg) → variable response due to polymorphism in CYP2D6 metabolizing 0-15% of codeine into morphine Strong opioids: - Morphine - Oxycodone - Fentanyl

Question 34

What are the ADRs of opioids?

Answer 34

ADRs of opioids: 1. **GIT e.g. N&V, constipation** 2. Hormonal effects 3. Depression 4. **Respiratory effects** 5. Overdose and death 6. Falls & fractures 7. **Sedation/drowsiness** → accidents 8. **Tolerance, physical dependence, addiction, withdrawal sx** 9. **Opioid-induced hyperalgesia (paradoxically)**

Question 35

What are the DDIs/drug-disease interactions of opioids?

Answer 35

DDI/Drug-disease interactions: 1. CNS depressants e.g. alcohol, BZDs, antidepressants 2. Kidney/liver insufficiency 3. Age>65y/o 4. Pregnancy 5. Substance use disorder

Question 36

What are the advantages and limitations of Opioids?

Answer 36

Advantages and limitations of Opioids Advantages of opioids: 1. Stronger analgesia than NSAID + Paracetamol combined → For severe pain when paracetamol & NSAIDs don’t work Limitations of opioids: 1. A lot of ADRs e.g. Addiction and abuse, sedation, respiratory depression