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S6 > Pharmacolgy S6 > Flashcards

Pharmacolgy S6 Flashcards

1
Q

Step 1 of asthma

A

Mild intermittent asthma

Short-acting b2 -agonists (salbutamol, terbutaline)

  • Used for symptom relief through reversal of bronchoconstriction
  • Prevention of bronchoconstriction i.e. on exercise
  • Short-acting b2 -agonists should only be used on an as-required basis
  • If used regularly, they reduce asthma control
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2
Q

Short-acting b2-agonists

Give examples of

A

salbutamol, terbutaline

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3
Q

Classes of b2-agonists

fast

onset,

short

duration

A

inhaled

inhaled

terbutaline

salbutamol

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4
Q

Classes of b2-agonists

slow onset,

short

duration

A

oral oral oral

terbutaline salbutamol

formoterol

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5
Q

Classes of b2-agonists

fast

onset,

long

duration

A

inhaled

formoterol

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6
Q

Classes of b2-agonists

slow onset,

long

duration

A

inhaled

salmeterol

oral

bambuterol

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7
Q

b2-agonist side-effects

A

Adrenergic i.e. tachycardia, palpitations, tremor……

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8
Q

Step 2 in ttt of asthma

A

Regular preventer therapy

Inhaled corticosteroids

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9
Q

Inhaled corticosteroids

A

Beclomethasone
Fluticasone

Budesonide

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10
Q

Step 3 –

A

Add on therapy

Before initiating a new drug therapy

Re-check patient’s medication compliance

• Check inhaler technique

-

Is it the right inhaler?

  • Are they still using it correctly?

• Eliminate trigger factors

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11
Q

Step 3

Add-on therapy

First choice

A

long-acting b2-agonist (formoterol, salmeterol)

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12
Q

Budesonide/formoterol

A

Symbicort

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13
Q

Fluticasone/formoterol

A

Seretide

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14
Q

Beclomethasone/formoterol

A

Fostair

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15
Q

Alternative step 3/step 4 add-ons

A
  • High dose ICS
  • Leukotriene receptor antagonists
  • Theophylline
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16
Q

Leukotriene Receptor Antagonists give examples

A

(Montelukast, Zafirlukast)

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17
Q

Leukotriene Receptor Antagonists

Side effects:

A

Angioedema Dry mouth Anaphylaxis Arthralgia Fever Gastric disturbances

Rarely a problem in clinical practice No important drug interactions

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18
Q

Theophylline mechanism of action

A

Inhibit PDE increase cAMP so no Ca influx no contraction ——-> bronchodilation

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19
Q

Methylxanthines
Give examples
Mechanism of action

A

theophylline, aminophylline)

Antagonise adenosine receptors Inhibit phosphodiesterase – increase cAMP relevant in vivo

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20
Q

Methylxanthines

Side effect

A

Narrow therapeutic window (10-20 mmol/L) Frequent side-effects – nausea, headache Potentially life-threatening toxic complications Important drug interactions – levels increased p450) inhibitors eg erythromycin, ciprofloxacin

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21
Q

Step 5 ?

A

Oral steroids

• Step 5+, Anti-IgE

– Strict criteria for use, very expensive. Potentially reduces exacerbation rates in patients not controlled on oral steroids

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22
Q

Drug delivery via inhaler devices

A

10 micron particles – deposited in the mouth and oropharynx 1-5 micron particles – most effective as they settle in

small airways

0.5 microns – too small. Inhaled to alveoli and exhaled without being deposited in the lungs

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23
Q

Acute severe asthma in adults

Severe

A
  1. Unable to complete sentences
  2. Pulse > 110 beats / min
  3. Respiration > 25 / min
  4. Peak Flow 33-50% of best or predicted
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24
Q

Life-threatening features of asthma

A

Previous plus any one of:

  • PEF <33%
  • sPO 2 <92
  • PaO 2 <8 kPa
  • PaCO 2 >4.5 kPa
  • Silent chest
  • Cyanosis
  • Feeble respiratory effort
  • Hypotension, bradycardia, arrhythmia
  • Exhaustion, confusion, coma

Near-fatal: PaO 2 >6 kPa, mechanical ventilation

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25
Q

Anticholinergic give examples

A

Iprotropium bromide ( ATROVENT )

A quaternary anticholinergic agent Bronchodilation develops more slowly and less intense than adrenergic agonists. Response may last up to 6 hours.

Useful add-on in actute severe asthma not responding to high dose b2-agonists

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26
Q

Treatment of acute severe asthma

A
  1. Oxygen, high flow
  2. Nebulised salbutamol – continuous if necessary, oxygen driven
  3. Oral prednisolone ~40 mg daily for 10-14 days
    - can be stopped without tailing down
  4. If not responding, add nebulised ipratropium bromide
  5. Consider i.v. magnesium sulphate 1.2-2.0 g over 20 min
  6. Consider IV aminophylline if no improvement and life threatening features not responding to above treatment (BEWARE if taking oral theophylline ).
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27
Q

Immunosuppressants

Agents

A
  • Corticosteroids
  • Azathioprine
  • Ciclosporin
  • Tacrolimus
  • Mycophenolate mofetil
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28
Q

disease-modifying a rheumatic drugs (DMARDs)

Agents ?

A
  • Methotrexate
  • Sulphasalazine
  • Anti-TNF agents
  • Rituximab
  • Cyclophosphamide (cytotoxic)
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29
Q

Corticosteroids mechanism of action as immunosuppressant

A
  • prevent interleukin (IL)–1 and IL-6 production by macrophages
  • inhibit all stages of T-cell activation
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30
Q

Azathioprine in practice

A
  • SLE & vasculitis -as maintenance therapy
  • RA - weak evidence for efficacy
  • Inflammatory bowel disease
  • Bullous skin disease
  • Atopic dermatitis
  • Many other uses as ‘steroid sparing’ drug
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31
Q

Azathioprine mechanism of action

A
  • Cleaved to 6-mercaptopurine (6-MP)

* functions as an anti-metabolite to decrease DNA and RNA synthesis

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32
Q

Azathioprine pharmacodynamics

A

6-MP is metabolized by thiopurine methyltransferase (TPMT)

  • TPMT gene highly polymorphic
  • Individuals vary markedly in TPMT activity
  • Those with low or absent TPMT levels are likely to develop myelosuppression
  • Therefore test this before prescribing
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33
Q

Azathioprine: adverse effects

A

• Bone marrow suppression

– Monitor FBC

• Increased risk of malignancy

– Esp transplanted patients -NHL

  • Increased risk of infection
  • Hepatitis

All immunosuppressants

– Monitor LFT

34
Q

Name 2 calcineurin inhibitors

A

Ciclosporin & tacrolimus

35
Q

Ciclosporin & tacrolimus mechanism of action

A

calcineurin inhibitors

36
Q

Ciclosporin & tacrolimus mechanism of action

A
  • active against helper T cells, preventing the production of IL-2 via calcineurin inhibition
  • Ciclosporin binds to cyclophilin protein
  • Tacrolimus binds to tacrolimus-binding protein
  • Drug/protein complexes bind calcineurin
  • Calcineurin normally exerts phosphatase activity on the nuclear factor of activated T cells. This factor then migrates to the nucleus to start IL-2 transcription
37
Q

Calcineurin inhibitors in practice

A
  • Widely used in transplant medicine
  • Also indicated for atopic dermatitis and psoriasis
  • Pimecrolimus only available as topical formulation use in atopic dermatitis
  • Not commonly used in rheumatology -concerns about toxicity
  • Ciclosporin useful in RA/SLE patients with cytopenias as it has no clinical effect on bone marrow
  • Monitor for toxicity -check BP and eGFR
38
Q

Calcineurin inhibitors: adverse effects

A
  • Nephrotoxicity
  • Hypertension
  • Hyperlipidemia
  • Nausea, vomiting, diarrhea
  • Hypertrichosis, gingival hyperplasia,
  • Hyperuricemia.
  • Multiple drug interactions are possible, primarily with agents affecting the cytochrome P-450 system
39
Q

Mycophenolate mofetil mechanism of action

A
  • Is a prodrug derived from fungus Penicillium stoloniferum
  • inhibits the enzyme inosine monophosphate dehydrogenase (required for guanosine synthesis)
  • impairs B- and T-cell proliferation
  • spares other rapidly dividing cells (because of the presence of guanosine salvage pathways in other cells)
40
Q

Mycophenolate acid adverse effects

A

Most common include nausea, vomiting, diarrhea

• Most serious ismyelosuppression

41
Q

Mycophenolate mofetil in practice

A

Primarily in transplantation

  • Good efficacy as induction and maintenance therapy for lupus nephritis
  • In transplantation medicine drug levels of the active metabolite mycophenolic acid (area under the curve) may be monitored
  • Toxicity may be precipitated by both renal and liver disease
42
Q

Cyclophosphamide
Mechanism of action

Indications

A

Alkylating agent -cross links DNA so that it cannot replicate

• Many immunological effects:

– suppresses T cell activity

– suppresses B cell activity

• Indications:

– lymphoma, leukaemia

– lupus nephritis

– Wegener’s granulomatosis

– Polyarteritis nodosum

43
Q

Cyclophosphamide pharmacodynamics

A
  • It is a prodrug
  • Converted in the liver (mixed function oxidase enzymes, cytochrome P450) to active forms that have chemotherapeutic activity..
  • The main active metabolite is 4-hydroxycyclophosphamide
  • 4-hydroxycyclophosphamide exists in equilibrium with its tautomer, aldophosphamide. Most of the aldophosphamide is oxidised to make carboxyphosphamide. A small proportion of aldophosphamide is converted into phosphoramide mustard (main active metabolite)
44
Q

Cyclophosphamide-

pharmacokinetics

A

Cyclophosphamide is excreted by the kidney

  • Acrolein, another metabolite is toxic to the bladder epithelium and can lead to hemorrhagic cystitis
  • This can be prevented through the use of aggressive hydration and/or Mesna.
45
Q

Methotrexate indications

A

Developed in 1940s (ALL)

  • Gold standard treatment for RA
  • Other indications

– malignancy

– psoriasis

– Crohn’s disease

• Also unlicensed roles: inflammatory myopathies, maintenance therapy in vasculitis, steroid-sparing agent in asthma

46
Q

Methotrexate: mechanism of action

A

Methotrexate competitively and reversibly inhibits dihydrofolate reductase (DHFR)

  • The affinity of methotrexate for DHFR is 1000X that of folate for DHFR.
  • Dihydrofolate reductase catalyses the conversion of dihydrofolate to the active tetrahydrofolate the key carrier of one-carbon units in purine and thymidine synthesis
  • Methotrexate, therefore inhibits the synthesis of DNA, RNA and proteins
  • Methotrexate acts specifically during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of the cell cycle. It therefore has a greater toxic effect on rapidly dividing cells (such as malignant and myeloid cells, and GI & oral mucosa), which replicate their DNA more frequently
47
Q

Methotrexate Mechanism of action in non-malignant disease

A

Mechanism of action in non-malignant disease e.g. RA, psoriasis is not clear

  • Mechanism is not via anti-folate action
  • Possible mechanisms include

– inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine, a purine nucleoside that is elaborated at injured and inflamed sites. Adenosine is a regulatory autocoid that is generated as a result of cellular injury or stress, interacts with specific G protein-coupled receptors on inflammatory and immune cells to regulate their function.

– the inhibition of T cell activation activation

– suppression of intercellular adhesion molecule expression by T cells

48
Q

Methotrexate: pharmacokinetics

A

Mean oral bioavailability is 33% (13-

  • Mean intramuscular bioavailability is 76%
  • Administered PO, IM or S/C
  • In patients taking PO with partial response or with nausea then swap to s/c
  • WEEKLY NOT DAILY DOSING, metabolized to polyglutamates with long half lives
  • 50% protein bound -NSAIDs displace
  • Renal excretion
49
Q

Methotrexate: adverse effects

A

mucositis

• marrow suppression

both respond to folic acid supplementation

  • hepatitis, cirrhosis,
  • pneumonitis (a hypersensitivity reaction)
  • infection risk
  • Highly teratogenic, abortifacient
50
Q

Methotrexate in practice

A

Well tolerated

  • 50% of patients continue the drug for >5 years, longer than any other DMARD
  • Improved QOL
  • Retardation of joint damage
  • Anchor drug for DMARD combinations
51
Q

Sulfasalazine (sulphasalazine)

A

A conjugate of a salicylate (5aminosalicylic acid, 5ASA) and a sulfapyridine molecule

  • Developed in 1940s
  • RA or ‘rheumatic polyarthritis’ believed to be infectious
  • Designed to relieve pain & stiffness (5-ASA = anti-inflammatory)
  • And to fight infection (sulfapyridine = sulfonamide)
52
Q

Sulfasalazine: immunological effects

A

• T cell

– inhibition of proliferation

– possible T cell apoptosis

– inhibition of IL-2 production

• Neutrophil

– reduced chemotaxis

– reduced degranulation

53
Q

Sulfasalazine: adverse effects

A

• Mainly due to sulfapyridine moiety

– myelosuppression

– hepatitis

– rash

• Milder side effects

– nausea

– abdo pain/vomiting

54
Q

Anti-TNF

Give examples

A

adalimumab

infliximab

Etanercept

55
Q

Effects of blocking TNF-a

A

 Inflammation

Cytokine cascade Recruitment of leukocytes to joint

elaboration of adhesion molecules

production of chemokines

 Angiogenesis VEGF and IL-8 levels  Joint destruction MMPs and other destructive enzymes Bone resorption and erosion Cartilage breakdown
“Decrease”

56
Q

Observational studies about anti TNF a

A

anti-TNF therapy does not appear to increase the overall risk of malignancy in RA

  • but BSBR data shows increased risk of new malignancy in those anti-TNF treated patients with prior malignancy
  • risk of serious infections is similar to that from other DMARDs
  • Anti-TNF increases risk of skin/soft tissue infections
  • TB reactivation and other intracellular bacterial infections post marketing surveillance
57
Q

Rituximab mechanism of action

A

Rituximab binds specifically to a unique cell-surface marker CD20, which is found on a subset of B cells but not on stem cells, pro-B cells, plasma cells or any other cell type

Rituximab: 3 key mechanisms for B cell depletion:

  • activation of complement mediated B cell lysis
  • initiation of cell mediated cytotoxicity via macrophages
  • induction of apoptosis
58
Q

Rituximab -long term considerations

A

development of hypogammaglobulinaemia and increased risk of infection
development of hypersensitivity or blocking immune responses e.g HACA

59
Q

Theophylline mechanism of action

A

Inhibit PDE increase cAMP so no Ca influx no contraction ——-> bronchodilation

60
Q

Methylxanthines
Give examples
Mechanism of action

A

theophylline, aminophylline)

Antagonise adenosine receptors Inhibit phosphodiesterase – increase cAMP relevant in vivo

61
Q

Methylxanthines

Side effect

A

Narrow therapeutic window (10-20 mmol/L) Frequent side-effects – nausea, headache Potentially life-threatening toxic complications Important drug interactions – levels increased p450) inhibitors eg erythromycin, ciprofloxacin

62
Q

Step 5 ?

A

Oral steroids

• Step 5+, Anti-IgE

– Strict criteria for use, very expensive. Potentially reduces exacerbation rates in patients not controlled on oral steroids

63
Q

Drug delivery via inhaler devices

A

10 micron particles – deposited in the mouth and oropharynx 1-5 micron particles – most effective as they settle in

small airways

0.5 microns – too small. Inhaled to alveoli and exhaled without being deposited in the lungs

64
Q

Acute severe asthma in adults

Severe

A
  1. Unable to complete sentences
  2. Pulse > 110 beats / min
  3. Respiration > 25 / min
  4. Peak Flow 33-50% of best or predicted
65
Q

Life-threatening features of asthma

A

Previous plus any one of:

  • PEF <33%
  • sPO 2 <92
  • PaO 2 <8 kPa
  • PaCO 2 >4.5 kPa
  • Silent chest
  • Cyanosis
  • Feeble respiratory effort
  • Hypotension, bradycardia, arrhythmia
  • Exhaustion, confusion, coma

Near-fatal: PaO 2 >6 kPa, mechanical ventilation

66
Q

Anticholinergic give examples

A

Iprotropium bromide ( ATROVENT )

A quaternary anticholinergic agent Bronchodilation develops more slowly and less intense than adrenergic agonists. Response may last up to 6 hours.

Useful add-on in actute severe asthma not responding to high dose b2-agonists

67
Q

Treatment of acute severe asthma

A
  1. Oxygen, high flow
  2. Nebulised salbutamol – continuous if necessary, oxygen driven
  3. Oral prednisolone ~40 mg daily for 10-14 days
    - can be stopped without tailing down
  4. If not responding, add nebulised ipratropium bromide
  5. Consider i.v. magnesium sulphate 1.2-2.0 g over 20 min
  6. Consider IV aminophylline if no improvement and life threatening features not responding to above treatment (BEWARE if taking oral theophylline ).
68
Q

Immunosuppressants

Agents

A
  • Corticosteroids
  • Azathioprine
  • Ciclosporin
  • Tacrolimus
  • Mycophenolate mofetil
69
Q

disease-modifying a rheumatic drugs (DMARDs)

Agents ?

A
  • Methotrexate
  • Sulphasalazine
  • Anti-TNF agents
  • Rituximab
  • Cyclophosphamide (cytotoxic)
70
Q

Corticosteroids mechanism of action as immunosuppressant

A
  • prevent interleukin (IL)–1 and IL-6 production by macrophages
  • inhibit all stages of T-cell activation
71
Q

Azathioprine in practice

A
  • SLE & vasculitis -as maintenance therapy
  • RA - weak evidence for efficacy
  • Inflammatory bowel disease
  • Bullous skin disease
  • Atopic dermatitis
  • Many other uses as ‘steroid sparing’ drug
72
Q

Azathioprine mechanism of action

A
  • Cleaved to 6-mercaptopurine (6-MP)

* functions as an anti-metabolite to decrease DNA and RNA synthesis

73
Q

Azathioprine pharmacodynamics

A

6-MP is metabolized by thiopurine methyltransferase (TPMT)

  • TPMT gene highly polymorphic
  • Individuals vary markedly in TPMT activity
  • Those with low or absent TPMT levels are likely to develop myelosuppression
  • Therefore test this before prescribing
74
Q

Azathioprine: adverse effects

A

• Bone marrow suppression

– Monitor FBC

• Increased risk of malignancy

– Esp transplanted patients -NHL

  • Increased risk of infection
  • Hepatitis

All immunosuppressants

– Monitor LFT

75
Q

Name 2 calcineurin inhibitors

A

Ciclosporin & tacrolimus

76
Q

Ciclosporin & tacrolimus mechanism of action

A

calcineurin inhibitors

77
Q

Ciclosporin & tacrolimus mechanism of action

A
  • active against helper T cells, preventing the production of IL-2 via calcineurin inhibition
  • Ciclosporin binds to cyclophilin protein
  • Tacrolimus binds to tacrolimus-binding protein
  • Drug/protein complexes bind calcineurin
  • Calcineurin normally exerts phosphatase activity on the nuclear factor of activated T cells. This factor then migrates to the nucleus to start IL-2 transcription
78
Q

Calcineurin inhibitors in practice

A
  • Widely used in transplant medicine
  • Also indicated for atopic dermatitis and psoriasis
  • Pimecrolimus only available as topical formulation use in atopic dermatitis
  • Not commonly used in rheumatology -concerns about toxicity
  • Ciclosporin useful in RA/SLE patients with cytopenias as it has no clinical effect on bone marrow
  • Monitor for toxicity -check BP and eGFR
79
Q

Calcineurin inhibitors: adverse effects

A
  • Nephrotoxicity
  • Hypertension
  • Hyperlipidemia
  • Nausea, vomiting, diarrhea
  • Hypertrichosis, gingival hyperplasia,
  • Hyperuricemia.
  • Multiple drug interactions are possible, primarily with agents affecting the cytochrome P-450 system
80
Q

Mycophenolate mofetil mechanism of action

A
  • Is a prodrug derived from fungus Penicillium stoloniferum
  • inhibits the enzyme inosine monophosphate dehydrogenase (required for guanosine synthesis)
  • impairs B- and T-cell proliferation
  • spares other rapidly dividing cells (because of the presence of guanosine salvage pathways in other cells)
81
Q

Mycophenolate acid adverse effects

A

Most common include nausea, vomiting, diarrhea

• Most serious ismyelosuppression

S6 (20 decks)

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