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3154 Finals > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

What is the mechanism of action of non-selective NSAIDs?

A

Inhibit both COX-1 and COX-2 enzymes, thereby inhibiting the production of prostaglandins (PGE2, PGI2 and TXA2)

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2
Q

State and explain the MOA of the broad pharmacological effects of NSAIDs (4)

A

1) Anti-inflammatory
- Inhibit vasodilation
- Dec vascular permeability –> dec swelling and pain a/w inflammation

2) Analgesic
- Inhibit production of prostaglandins, which sensitise nociceptive fibres to stimulation by other inflammatory mediators (decr signal amplification)
- May have some additional effects on CNS

3) Anti-pyretic
- Inhibit PGE2 synthesis by blocking COX in the hypothalamus, resetting the body’s thermostat
- Does not alter normal body temperature

4) Anti-platelet (most sig for Aspirin)
- Inhibits TXA2 production by platelets, thereby inhibiting platelet aggregation

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3
Q

List the adverse effects of non-selective NSAIDs (6)

A

1) Gi: Bleed/ulcers
2) Renal: Hypertension, AKI
3) Asthma: Bronchospasm
4) Increased bleeding risk
5) Pseudo-allergy
6) Reye’s syndrome (very rare)

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4
Q

Is it true that coxibs (selective COX-2 inhibitors) have no side effects, since COX-2 enzymes are involved only in inflammatory responses?

A

No.

  • At higher doses, coxibs still have risk of adverse effects (some degree of COX-1 inhibition)
  • There is constitutive COX-2 in kidneys, synovium and female reproductive tract as well
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5
Q

List the adverse effects due to COX-2 inhibition (5).

A

1) Renal toxicity
- Expression of COX-1 and COX-2 in kidney
- Renal effects causing HTN

2) Delayed follicular rupture

3) Impaired wound healing
- May exacerbate pre-existing ulcers
- Caution in existing ulcers/RF, post-surgical analgesia, non-union of fractures, bone repair
- Wait for wound to heal before giving coxibs

4) Increased thrombotic risk
- Relative inc in TXA2, promoting platelet aggregation
- Caution in high thrombotic risk (e.g. elderly)

5) MI and stroke
- Renal effects causing HTN + prothombotic effects
- Inc risk of heart attack, failure and stroke
- Caution in elderly, hx of CBV and CV disease

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6
Q

What are the contraindications for NSAIDs? (7)

A
  1. Severe renal impairment (eGFR<30)
  2. Severe heart failure
  3. Active GI ulcers/bleeds
  4. Bleeding disorders e.g. hemophilia
  5. (Relative) Concomitant use of corticosteroids, antiplatelets, anticoagulants
  6. Pregnancy (third trimester)
  7. Multiple risk factors for NSAID toxicity
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7
Q

Which NSAID is preferred for use in dysmenorrhea?

A

Naproxen

  • Greater free fraction in females
  • BD dosing (half-life 12-14h)
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8
Q

Which NSAID has long half-life in synovial fluid and can be applied topically?

A

Diclofenac

(Additionally has short plasma half-life, which leads to lower risk of GI effects)

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9
Q

Which NSAIDs are preferred and avoided in high risk of CV toxicity?

A
  • Avoid diclofenac and COX-2 selective NSAIDs
  • Use celecoxib, naproxen or ibuprofen, but limit to 5 days or less. If cannot use any of the 3, use paracetamol.
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10
Q

Which NSAIDs are preferred and avoided in high risk of GI toxicity?

A
  • Avoid non-selective NSAIDs
  • Use a COX-2 selective NSAID, but with caution
  • Consider co-prescribing GI protectant (e.g. PPI)
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11
Q

Which NSAIDs are preferred and avoided in high risk of bronchospasm/pseudo-allergy?

A
  • Avoid non-selective NSAIDs
  • Use a COX-2 selective NSAID, but with caution
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12
Q

What is the (postulated) mechanism of action of paracetamol?

A

CNS-selective COX inhibition

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13
Q

What are the pharmacological effects of paracetamol?

A
  • Good analgesic
  • Potent antipyretic action
  • NOT anti-inflammatory at clinical doses
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14
Q

What are some advantages of paracetamol use over other analgesics? (4)

A
  • Low incidence of ADRs
  • Spares the GIT
  • Few DDIs
  • Relatively safe for pediatric use
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15
Q

What are some disadvantages of paracetamol use compared to other analgesics? (3)

A
  • Weak anti-inflammatory effects
  • Toxicity at higher doses (nausea, vomiting, hepatotoxicity)
  • Allergic skin reactions may occur
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16
Q

What are some cautions to be taken with paracetamol? (3)

A
  • Hepatic dysfunction or alcohol abuse
  • Dose reduction in underweight, significant liver disease, cachectic or frail
  • Overdose. Refer to ED if 10g or more in 24h; increased risk of harm at 4g or more in 24h
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17
Q

What are some various ways of paracetamol + NSAID combination and state their beneficial effects? (2)

A

(Alternating) Sustain antipyretic effect

(Taken together) Synergistic effect for analgesia

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18
Q

Describe the clinical use of opioids as an analgesic (wrt to place in tx, presence of anti-inflammatory effect and dosing and risks involved with its use).

A
  • NOT first-line for pain
  • Not anti-inflammatory
  • Use lowest effective dose of weakest effective opioid for shortest duration
  • Significant risk of adverse effects, diversion and misuse
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19
Q

List the opioids in increasing order of strength/potency.

A

Tramadol < codeine < morphine < oxycodone < fentanyl

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20
Q

List the adverse effects of opioid analgesics (8).

A
  1. GI effects (N/V/C)
  2. Hormonal, respiratory effects
  3. Depression
  4. Overdose and death
  5. Falls and fractures
  6. Sedation, drowsiness
  7. Tolerance, physical dependence, addiction, withdrawal
  8. Opioid-induced hyperalgesia

80% will develop 1 or more of the above

21
Q

What are the risk factors for ADRs associated with opioid analgesics? (6)

A
  1. Combi with other CNS depressants
  2. Other comorbidities (e.g. mental disorders)
  3. Renal/hepatic insufficiency, age >65
  4. Pregnancy
  5. Personal or FH of substance use
  6. Risk of diversion/opioid use disorder
22
Q

List the 3 prostanoids and state which one inhibit platelet aggregation and which one promotes platelet aggregation

A

Prostacyclin (inhibit platelet aggregation), Prostaglandin, Thromboxane (promote platelet aggregation)

23
Q

State the difference in prostanoids produced by COX-1 vs COX-2 and its implication

A

COX-1 produce thromboxane while COX-2 does not -> COX-2 selective NSAID have higher thrombotic risk

24
Q

State the 2 prostanoids that have a role in kidney and the various effects caused by the inhibition of their synthesis by NSAIDs. (7)

A

Inhibition of PGE2:
- Inc sodium and water retention
- Edema and HTN

Inhibition of PGI2:
- AKI (cause vasoconstriction of afferent arteriole)
- Decreased secretion of renin and aldosterone -> lead to hyperkalemia (and incr sodium excretion but < than sodium reabsorption from PGE2 inhibition = overall Na retention)

25
Q

Explain how use of NSAID may cause/worsen asthma in asthmatic patients

A

Shunting of Arachidonic acid from COX pathway to increase Leukotrienes that induce bronchospasm

26
Q

ADRs that occur at low doses of NSAIDs are due to ____ while those that occur at high doses are due to ____

A

COX inhibition, chemical structure

27
Q

What is the approximate dose at which ADRs due to salicylate chemical structure start to occur?

A

1-6g (plasma conc > ~500mg/L)

28
Q

Which liver enzyme responsible for formation of toxic metabolite of Paracetamol?

A

CYP2E1

29
Q

State the MOA of Hyaluronic Acid and its place in treatment of OA.

A

Serve as protective coating of cartilage, helping with shock absorption, traumatic energy dissipation, lubrication, and reduces pain and stiffness

(From YKZ and UTD) Generally not recommended for symptomatic treatment of OA due to invasiveness, poor efficacy and cost.

30
Q

MOA of Methotrexate

A

Major MOA:
- Inhibits 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/ IMP cyclohydrolase (ATIC) leading to increased adenosine and hence incr binding to Adenosine receptors which possess anti-inflammatory effect -> Decrease in pro-inflammatory cytokines, adhesion molecules, chemotaxis and phagocytosis

Minor MOA:
- Inhibit DHFR and thymidylate synthase leading to anti-proliferative effects on T cell and inhibit macrophage function

31
Q

A physician intends to start Folate for a patient on MTX as rescue therapy. Comment on the suitability of this.

A

o Folate is cheaper but high doses too overcome MTX inhibition are required as folate does not efficiently rescue toxicity due to depletion of N5, N10-Methylene-FH4 as dihydrofolate reductase is inhibited.

o Folinic acid or folinate (NS-formyl-FHA) is rapidly converted to N5, N10-Methylene-FHA. As DHFR activity is bypassed, it is more efficient at rescuing methotrexate toxicity.

32
Q

Purported MOA of Sulfasalazine (2)

(Not LO)

A

o Decreased IgA and IgM rheumatoid factors
o Suppression of T and B cells, and macrophages leading to
o Decrease in inflammatory cytokines e.g., IL-1ß, TNF and IL-6

33
Q

ADR of Sulfasalazine (6)

A

N/V, headache, rash, haemolytic anaemia, neutropenia, reversible infertility in men

34
Q

MOA of Leflunomide (NOT LO)

A

o Inhibits dihydroorotate dehydrogenase
o Decrease in pyrimidine synthesis and growth arrest at G1 phase
o Inhibits T cell proliferation and B cell autoantibody production
o Inhibits NF-kB activation pro-inflammatory pathway

35
Q

MOA of Hydroxychloroquine (Not LO)

A
  • Reduced MHC Class II expression and antigen-presentation
  • Reduced TNF-a and IL-1, and cartilage resorption
  • Antioxidant activity (idk how this helps but wtv)
36
Q

MOA of Tofacitinib

A
  • Janus kinase (JAK) pathway inhibitor
  • Blocks cytokine production by blocking JAK/STAT-activation of gene transcription
37
Q

ADR of Tofacitinib (3)

A
  • Cytopenia including neutrophils, lymphocytes, platelets and natural killer cells
  • Immunosuppression resulting opportunistic infections [increased risk of herpes zoster infection (especially in Asian population)]
  • Anaemia (affects JAK2 activitation by erythropoietin)
  • Hyperlipidemia: increases in total, LDL and HDL cholesterol and trigylcerides

Pancytopenia, Immunosuppression, Hyperlipidemia (HIP)

38
Q

List example of Anti-TNF mAb

A

infliximab, adalimumab, Etanercept

39
Q

MOA of Anakinra

A

Binds to IL-1 receptors and block IL-1 signalling

40
Q

MOA of Abatacept (not in LO)

A

Bind to CD80 and 86, preventing CD28 activation and hence preventing T cell activation

41
Q

MOA of Rituximab (not in LO)

A

Depletes CD20+ B cells by binding to CD20 and inducing pathways leading to B cell death

42
Q

MOA of Tocilizumab (NOT LO)

A

Prevents binding of IL-6 to IL-6Rα and homodimerization of IL-6Rβ signaling

43
Q

State which biologic DMARD is associated with the most CYP interactions and why

A

Tocilizumab causes decr IL-6 which ↑ expression of CYP enzymes.

(Normally IL-6 ↓ expression of these CYP450 enzymes)

44
Q

ADR of Anakinra (2)

A

Infections, injection site reactions

45
Q

ADR of Tocilizumab (7) (NOT LO)

A

Infections, skin eruptions (rash), stomatitis, fever, neutropenia, increase in ALT/AST, hyperlipidaemia

46
Q

ADR of Abatacept (2) (not in LO)

A

Respiratory infection in COPD, ↑ lymphoma incidence

47
Q

ADR of Rituximab (2) (not in LO)

A

Rash in first dose, respiratory infection in COPD

48
Q

ADR of Anti-TNF mAb (6)

A

Respiratory infection and skin infection,

Increased risk of lymphoma, optic neuritis,

Exacerbation of multiple sclerosis, leukopenia, aplastic anemia

49
Q

Contraindication of Anti-TNF mAb

A

Live vaccination, active TB

3154 Finals (7 decks)

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