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Pharmacology Year 1 > Drugs for Inflammation > Flashcards

Drugs for Inflammation Flashcards

1
Q

What are NSAIDs?

A

NSAIDs can be defined as a class of drugs that have in common the ability to act as reversible inhibitors of the conversion of arachidonic acid to prostanoids by the enzyme cyclooxygenase (COX).

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2
Q

What are the two categories of NSAIDs?

A
  • Those that are non-selective for the two COX isoforms (COX-1 and COX-2) e.g. ibuprofen, indomethacin, diclofenac, naproxen.
  • Those that are highly selective for COX-2 only e.g. celecoxib.
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3
Q

What are corticosteroids?

A

corticosteroids e.g. prednisolone, another category of anti-inflammatory drugs which are also considered to be a variety of immunosuppressant drug because their primary mechanism of anti-inflammatory action is suppression of the immune response.

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4
Q

What is the exception to the NSAID definition?

A

The exception is aspirin which produces inhibition that is effectively irreversible, requiring the synthesis of new enzyme for restoration of prostanoids production.

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5
Q

What are the classifications of NSAIDs based on their chemical origin? (5)

A

 Salicylates: acetylsalicylic acid (aspirin), salicylic acid

 Propionic acid derivates: Ibuprofen, Naproxen, Ketoprofen

 Acetic acid derivatives: Indomethacin, diclofenac, Ketorolac

 Enolic acid derivatives: Phenylbutazone, piroxicam, meloxicam

 Coxibs: celecoxib

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6
Q

What is the arachidonic acid pathway involving inflammatory effects? (4)

A
  • Arachidonic acid is released from membrane phospholipids by action of enzyme phospholipase A2.
  • Phospholipase A2 activity up regulated during inflammation in calcium dependent mechanism in response to a variety of mediators, including bradykinin.
  • After release, arachidonic acid is converted into range of active molecules in a series of enzyme dependent redox reaction.
  • The best-known enzyme is COX which is the rate-limiting enzyme involved in the conversion of arachidonic acid to prostaglandin H2, the precursor of all of the prostanoid mediators.
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7
Q

What is PGE2?

A

The most abundant prostaglandin that supports cortical blood flow in the kidney and serves to maintain the resistance of the gastric mucosa to acid-induced ulceration (Gastroprotection)

PGE2 reduces the secretion of stomach acid, maintains a protective mucosal layer by increasing mucous production and improves local blood flow.

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8
Q

What is COX-1?

A

COX-1 is a constitutive (constantly present) enzyme found widely around the body and is responsible for maintaining the production of prostaglandins in several organs.

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9
Q

What is prostacyclin?

A
  • Prostacyclin, a vasodilator and, inhibitor of platelet activity
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10
Q

What is COX-2?

A

COX-2 is synthesized by inflammatory cells (e.g. mast cells and neutrophils) to provide prostaglandins which promote inflammation by increasing vascular permeability, attracting leukocytes, and causing pain.

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11
Q

Why where coxibs developed?

A

These were developed with the aim of reducing the rate of adverse effects (e.g. gastric ulceration) caused by inhibiting the production of housekeeping prostaglandins.

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12
Q

How do corticosteroids act on the arachidonic acid pathway?

A

Corticosteroids also have an important inflammatory effect on the arachidonic acid pathway but do so by inhibiting the transcription of several important pro-inflammatory enzymes including phospholipase A2 and cyclooxygenase.

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13
Q

What are the pharmacokinetics of ibuprofen?

A
  • Rapidly absorbed from the GI tract, but at a slower rate with food.
  • Peak plasma concentration is reached after around 1-2 hours.
  • Phase I metabolism in the liver to from hydroxylated and carbonylated derivatives
  • Phase II metabolism form a glucuronide conjugate, which is subsequently excreted in urine
  • Plasma half-life of ibuprofen in healthy subjects is around 1-2 hours.
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14
Q

What are the clinical effects, indications, contraindications and cautions of NSAIDs?

A
  • Clinical effects of NSAIDs: Anti-inflammatory with secondary pain relief.
  • Clinical indications: Painful inflammatory conditions including rheumatic diseases (e.g. RA, OA), other musculoskeletal disorders, menstrual pain, dental pain, headache, as adjunct to postoperative analgesia, pyrexia.
  • Contra-indications: Active GI bleeding or ulceration, or previous NSAID related episodes, severe heart failure, pregnancy.
  • Cautions: elderly, allergic disorders, coagulopathy, heart failure, increased cardiovascular risk.
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15
Q

What is unique about clinical use of aspirin? Why is this?

A

Aspirin used in acute managements of cardiovascular events (e.g. MI, stroke), secondary prevention of cardiovascular disease, prevention of pre-eclampsia.

This is because:
Aspirin inhibits cyclooxygenase irreversibly to prevent platelet aggregation at doses that are much lower than necessary to have its anti-inflammatory effects, hence why lose-dose aspirin is indicated in management of acute cardiovascular disease and secondary prevention.

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16
Q

What is the formulation of NSAIDS?

A

-By mouth: immediate-release or modified-release tablets, oral suspension.

-Transdermal: ibuprofen gel, diclofenac gel

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17
Q

What are some common doses of NSAIDs?

A
  • ibuprofen 200-400 mg PO 3x daily
  • diclofenac sodium 75-150 mg daily in 2-3 doses
  • Naproxen 500mg-1g daily in 1-2 does
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18
Q

What are some common combination preparations of NSAIDs?

A
  • naproxen with esomeprazole
  • diclofenac sodium with misoprostol
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19
Q

What are the adverse effects of NSAIDs on the gastrointestinal system? How can you manage these effects?

A
  • related to the inhibition of COX-1 which normally generates prostaglandin-E2 that contributes to gastric mucosal protection against the high concentration of gastric acid.
  • Adverse effects range from mild dyspepsia to massive hemorrhage from a perforated gastric ulcer.
  • Gastro Toxicity is reduced among patients taking celecoxib.
  • Alternative strategy is to co-prescribe a proton-pump inhibitor e.g. omeprazole which reduces gastric acid secretion.
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20
Q

What are the effects of NSAIDs on renal function?

A
  • under normal condition renal function dependent on the vasodilation effects of PGE2 and prostacyclin which supports cortical blood flow.
  • Prostaglandins play a key role in the regulation of afferent and efferent arterial tone in the glomerulus which is important in maintaining renal function in hypovolemic states.
  • Inhibition of prostacyclin production of NSAIDs can lead to decreased glomerular filtration rate, salt and water retention, and acute kidney injury.
  • This is particularly important in the elderly who often have a degree of renal impairment at times of dehydration like acute illness or secondary to the effects of diuretics and when renal blood flow is compromised by other factors such as drugs that block the renin-angiotensin system.
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21
Q

What are the effects of NSAIDs on the respiratory system? Why is this?

A
  • around 10% of patients with asthma may experience an exacerbation on exposure to NSAIDs, possibly due to inhibition of arachidonic acid metabolic by COX leads to an increase in production of leukotrienes which act as bronchoconstrictors.
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22
Q

How can NSAIDs increase bleeding time?

A
  • due to the inhibition of the COX-1 isoform which normally produces thromboxane A2 that increases platelet adhesiveness and vasoconstriction. (explains therapeutic effects of aspirin which irreversibly inhibits platelet cyclooxygenase rendering it ineffective for the remainder of 10 day life).
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23
Q

What are the pharmacodynamic interactions of NSAIDs?

A
  • Gastric musoca – drugs that also exhibit Gastrotoxicity or favor bleeding: antiplatelet drugs, aspirin, anticoagulants, corticosteroids, selective serotonin re-uptake inhibitors.
  • Renal function – drugs that also have adverse renal effects: ACE inhibitors, angiotensin receptor antagonists, diuretics
  • Blood pressure: attenuates beneficial effects of antihypertensive drugs
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24
Q

What are the pharmacokinetic interactions of NSAIDs?

A

Where renal excretion of drugs affected which can cause accumulation to a toxic concentration: methotrexate, lithium.

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25
Q

What warnings to patients are necessary when prescribing NSAIDs?

A
  • Patients at increased risk of cardiovascular events as NSAIDs may increase that risk.
  • Patients taking topic preparations, wash hands immediately after use, excessive exposure to sunlight of the area treated in order to avoid possibility of photosensitivity.
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26
Q

What monitoring arrangements are necessary for NSAIDs?

A
  • beneficial effects: pain relief
  • Adverse effects: Dyspepsia, renal impairment, hyperkalaemia
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27
Q

What are Mineralocorticoids?

A

Mineralocorticoids (e.g. aldosterone) released from the zona glomerulosa in response to circulating angiotensin II. Names because of their effect on electrolyte homeostasis.

28
Q

What are Glucocorticoids?

A

Glucocorticoids (e.g. cortisol) released from the zona fasciculata in response to ACTH (anterior pituitary adrenocorticotrophic hormone). Named because of their impact on the glucose metabolism.

29
Q

What are sex steroids?

A

Sex steroids (mainly precursors androgens) released from the zona reticularis also in response to ACTH.

30
Q

How are glucocorticoids classified?

A
  • Glucocorticoids can be divided into those that occur naturally that are secreted by the adrenal gland (e.g. hydrocortisone aka. cortisol) and those that are synthetic.
  • The synthetic group of glucocorticoids can be further divided up into those that resembles hydrocortisone (e.g. prednisolone), and those that resemble betamethasone (e.g. dexamethasone) and the acetonides (e.g. budesonide).
31
Q

Basic way that corticosteroids elicit their actions?

A

Corticosteroids elicit their actions through their binding to cytosolic glucocorticoid receptors (GRs).

32
Q

How do corticosteroids act on cytosolic glucocorticoid receptors leading to GR binding to target genes?

A
  • glucocorticoids are sufficiently lipophilic to cross the cell membrane.
  • Resting GRs bound to heat shock proteins (HSPs)
  • Ligand binding causes detachment from HSPs followed by translocation to the nucleus where it dimerizes with another ligand bound glucocorticoid receptor and binds to a sequence of target genes.
33
Q

How do glucocorticoids interact with DNA?

A
  • Ligand bound GRs bind to target gene sequences (glucocorticoid response elements).
  • Multiple co-activators or repressors recruited to up or down regulate gene expression.
  • GRs exist in different isoforms (e.g. GR-alpha the dominant glucocorticoid receptor isoform and the primary mediator, GR-beta which possess partial agonist activity and acts as a competitive negative regulator of GR signaling) with varying agonist properties.
34
Q

What are the non-genomic effects of glucocorticoids?

A

inhibition of the pro-inflammatory transcription factors AP-1 and NF-kB.

35
Q

What are the steps 5 of the physiological functions of the pituitary-adrenal axis?

A
  • Hypothalamus produces corticotropin releasing hormone (CRH) in response to many distinct circadian, neurosensory, blood-borne, and limbic signals.
  • CRH in return acts on the anterior pituitary gland resulting in the secretion of adrenocorticotrophic hormone (ACTH) into the circulation.
  • ACTH acts on the zona fasciculata of the adrenal gland resulting in the synthesis and release of cortisol.
  • Within the circulation cortisol is primary bound to corticosteroid binding protein (CBG) with only a small portion existing as free biologically active cortisol.
  • Circulating cortisol regulates both CRH and ACTH release at the hypothalamus and pituitary respectively – negative feedback loop.
36
Q

How do cytokines influence CRH release? Why is this important?

A
  • The secretion of CRH, ACTH and cortisol is also up-regulated by the direct actions of cytokines (e.g. TNF-alpha, IL-1beta, IL-6 and IFN-alpha/beta)
  • Cytokines are release by immune cells (e.g. macrophages) during infection, acute inflammation, and autoimmune disease
    .
  • This action is thought to be important in protecting the body from detrimental effects of excessive inflammatory tissue damage and autoimmune shock.
37
Q

What is CRH?

A

Corticotropin releasing hormone.

38
Q

What is addison’s disease?

A

Addison’s disease = causes underactivity of the adrenal gland

39
Q

What is cushing’s disease?

A

Cushing’s disease = excessive secretion of corticosteroids.

40
Q

What happens when cortisol is absent in normal immunological function?

A

When absent there is hypertrophy of the lymphoid tissues (thymus, spleen, lymph nodes) because cortisol induces lymphocyte apoptosis.

41
Q

What happens physiologically when corticosteroids are used therapeutically? (3)

A

When used therapeutically corticosteroids
- decrease the secretion of interleukin-1 and other mediators of immune response
- inhibit lymphocyte participation in delayed hypersensitivity reactions
- interfere with the rejection of immunologically incompatible graft tissue.
- High doses of corticosteroids also inhibit immunologic synthesis, kill B cells, and decrease production of components of the complement system.

42
Q

how do corticosteroids suppress the full inflammatory reaction to infectious, physical, or immunological events: (4)

A
  • Inhibit early inflammatory events like oedema, cellular exudation, fibrin deposition, capillary dilation, migration of leukocytes and phagocytic activity.
  • Corticosteroids prevent the increase in expression of intercellular adhesion molecules (e.g. ELAM-1) and induce lipocortin, a protein inhibitor or phospholipase A2 (PLA2).
  • PLA2 activity is required to release arachidonic acid for prostaglandin synthesis , so this action reduces the influence of these important pro-inflammatory mediators.
  • Corticosteroids also stabilize lysozymes, thereby decreasing the release of hydrolytic enzymes and histamine, and decrease binding of chemokines that attract leukocytes.
43
Q

How do Glucocorticoids impact glucose metabolism: (3)

A
  • Stimulate the conversion of protein to carbohydrate through hepatic gluconeogenesis.
  • Promote the storage of carbohydrate as glycogen.
  • Decrease facilitated uptake of glucose int the peripheral tissues, which provides more glucose for glycogen storage in the liver.
44
Q

Why is cortisol required at physiological concentrations?

A

Cortisol is required at physiological concentration for health function of muscles and bones, with its influence being generally catabolic.

45
Q

What does catabolic mean?

A

promoting metabolic activity concerned with the breakdown of complex molecules (such as proteins or lipids) and the release of energy.

46
Q

What are the actions of corticosteroids on the CNS? How does this relate to addison’s disease?

A

Corticosteroids have CNS actions with a positive influence on mood, behaviour, electroencephalograph patterns, memory consolidation, and brain excitability.

-> Patients with Addison’s disease are subject to apathy and depression, symptoms that are alleviated by glucocorticoid therapy.

47
Q

What is the effect of corticosteroids on the kidneys?

A

Cortisol tends to increase sodium and water retention and potassium excretion, both in the renal tubules and the GI tract.

These effects are much less pronounced than those produced by primary mineralocorticoid aldosterone which is released from the zona glomerulosa of the adrenal gland.

Cortisol also favors calcium excretion in the renal tubules.

48
Q

What is the effect of corticosteroids on the cardiovascular system?

A
  • As a result of corticosteroid effect on plasma volume, electrolyte retention, adrenaline synthesis, and angiotensin levels, which together contribute to the maintenance of normal blood pressure and cardiac output.
  • Corticosteroids encourage the adrenergic effects of catecholamines and stimulate the synthesis of adrenaline from noradrenaline.
49
Q

What happens when corticosteroids are used for extended periods of time?

A

The pharmacological actions of corticosteroids mimic or exaggerate those of endogenous glucocorticoids, however they also suppress the release of CRH and ACTH and cortisol therefore after prolonged treatment there is a degree of atrophy of the hypothalamic-pituitary-adrenal axis meaning that patients become dependent on the exogenous corticosteroid for their physiological requirements. This axis takes time to recover function

50
Q

What are the clinical effects, indications and cautions of corticosteroids?

A

Clinical effects of corticosteroids: anti-inflammatory and Immunosuppression.

Clinical indications: Asthma, COPD exacerbations, RA and other inflammatory arthropathies, IBD, nephrotic syndrome, Autoimmune diseases (e.g. myasthenia gravis, idiopathic thrombocytopenia purpura), vasculitis, Allergic emergencies, Local application (e.g. eye, ear, skin, joints), replacement therapy.

Cautions:
- Heart failure or hypertension – risk of salt and fluid retention.
- Diabetes mellitus – worsening glucose control
- Peptic ulcer – negative impact on gastro-protection
- Untreated infection or a past history of TB
- Osteoporosis
- psychiatric disorders – known impact on mood and psychosis.
- recent surgery that necessitates healing of anastomoses – negative impact on wound healing.

51
Q

What are some common formulations of corticosteroids?

A
  • PO: hydrocortisone, prednisolone
  • IV/IM hydrocortisone, methylprednisolone, dexamethasone
  • Inhaled: beclomethasone, fluticasone
  • Topical: Hydrocortisone, betamethasone
  • Eye, ear, intra-articular.
52
Q

What are some adverse effects of corticosteroids on the Immune system?

A

o increased risk of infection due to immunosuppression

o Tuberculosis reactivation

53
Q

What are some adverse effects of corticosteroids on the GI system

A

o Peptic ulceration due to increased gastric acid secretion and blood flow, and decreased rate of gastric cell proliferation.

o Increased appetite and weight

54
Q

What are some adverse effects of corticosteroids on the Cardiovascular system?

A

o hypertension due to sodium and water retention and calcium loss.

o fluid retention

o electrolyte imbalance

55
Q

What are some adverse effects of corticosteroids on the Endocrine system

A

o insulin resistance/diabetes due to effect on glucose metabolism

o Adrenal suppression

56
Q

What are some adverse effects of corticosteroids on the Skin?

A

o thinning
o Hirsutism
o Cushingoid appearance

57
Q

What are some adverse effects of corticosteroids on the Musculoskeletal system? (5)

A
  • Osteoporosis, Bone fractures – direct effects on OC, OB, and OC function, increased renal calcium excretion and decreased GI Calcium absorption, hence reduced serum calcium concentration, increasing secretion of PTH. Also increase sensitivity to PTH effect, primarily stimulation of osteoclast activity.
  • Osteonecrosis (aseptic or avascular) and spontaneous tendon rupture through effects on collagen metabolism.
  • Myopathy involving muscle weakness and wasting because of altered electrolyte status and the catabolic effects on protein metabolism.
  • growth suppression in children as a result of decreased maturation of the epiphyseal plates and decreased long bone growth.
  • healing impaired by preventing capillary and fibroblast proliferation, deposition of collagen.
58
Q

What are some adverse effects of corticosteroids on the eyes?

A

posterior subcapsular cataracts, increased intraocular pressure.

59
Q

What could happen if corticosteroid treatment is abruptly withdrawn or increased requirements?

A

Abrupt withdrawal of treatment (or increased requirements due to stress) may precipitate acute adrenal insufficiency (Addisonian crisis):

60
Q

What are the symptoms, signs and progression of an addisonian crisis?

A
  • Symptoms: abdominal pain, profound weakness, headache, nausea, vomiting
  • Signs: Hypotension, Hypoglycemia
  • Life-threatening: shock -> coma -> seizures -> death.
61
Q

What should you inform patients about when prescribing corticosteroids?

A
  • Doses should be increased during significant intercurrent illness, following trauma and during surgery.
  • patients should carry a ‘steroid treatment card’.
  • Planned withdrawal of corticosteroid therapy should be gradual.
  • prolonged exposure to exogenous corticosteroids suppresses the hypothalamic-pituitary-adrenal axis.
62
Q

Pharmacodynamic interactions of corticosteroids?

A

Pharmacodynamic interactions:
- other drugs that exacerbate the potential adverse effects
- Drugs that also exhibit Gastro Toxicity such as NSAIDs
- Drugs that either precipitate hypokalemia or that are more likely to precipitate arrhythmias when it occurs.
- Vaccinations with live viruses where there is a risk of more generalized infection occurring.

63
Q

Pharmacokinetic interactions of corticosteroids?

A
  • Occur theoretically with drugs that alter the rate of metabolism of corticosteroids.
  • the exposure to system corticosteroids may be reduced by drugs that enhance CYP3A4 metabolism (e.g. carbamazepine)
  • May be increased by those that inhibit metabolism (e.g. ketoconazole, clarithromycin).
  • In practice, pharmacokinetic interactions are rarely important.
64
Q

What warning should be given about corticosteroids?

A
  • Immunosuppression – increased susceptibility to infection

-Adrenal suppression
courses longer than 3 weeks: Avoid abrupt withdrawal, Inform other healthcare staff when receiving care.

  • Mood and behavior changes: Confusion, irritability, delusion, and suicidal ideation.
65
Q

What monitoring arrangements are necessary for corticosteroid treatments?

A

beneficial effects:
- progress of the inflammatory disease
- Symptoms (e.g. pain, function)
- Examination findings (e.g. joint inflammation)
- Investigations (e.g. CRP C reactive protein, ESR erythrocyte sedimentation rate)

Adverse effects:
- blood pressure
- Blood glucose.

Use at lowest dose for shortest period of time.

Pharmacology Year 1 (6 decks)

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