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Imperial > 54. Asthma & Respiratory Pharmacology > Flashcards

54. Asthma & Respiratory Pharmacology Flashcards

1
Q
A
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2
Q

Name the three parts of the adrenal cortex and the steroids that each produces.

A

Zona Glomerulosa – Aldosterone Zona Fasciculata – Cortisol Zona Reticularis – Sex Steroids

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3
Q

What hormone controls the production of adrenal sex steroids?

A

ACTH

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4
Q

What controls the production of aldosterone?

A

Angiotensin II

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5
Q

State four triggers of aldosterone release

A

Hyperkalaemia Hyponatraemia Drop in renal blood flow Beta-1 stimulation

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6
Q

What is the principle action of aldosterone?

A

Increases Na+ reabsorption Increases K+ excretion

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7
Q

State three differences between glucocorticoid receptors and mineralocorticoid receptors.

A

GRs are widely distributed; MRs have a discrete distribution GRs are selective for glucocorticoids; MRs cannot distinguish between cortisol and aldosterone GRs have a low affinity for cortisol; MRs have a high affinity for cortisol

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8
Q

Describe how MRs are protected from cortisol stimulation.

A

There is an enzyme called 11-beta hydroxysteroid dehydrogenase-2, which converts cortisol to the inactive cortisone to prevent it from interacting with mineralocorticoid receptors. NOTE: 11-beta-HSD-1 converts cortisone back to cortisol

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9
Q

Why do you get hypokalaemia in Cushing’s syndrome?

A

In Cushing’s syndrome there is so much cortisol that it overloads the 11-beta-HSD-2 system so the cortisol binds to the mineralocorticoid receptors and has mineralocorticoid effects.

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10
Q

Name three glucocorticoid drugs in order of decreasing mineralocorticoid activity.

A

Hydrocortisone (highest mineralocorticoid activity) Prednisolone Dexamethasone

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11
Q

What does prednisolone tend to be used for?

A

Immunosuppression

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12
Q

What does dexamethasone tend to be used for?

A

Acute anti-oedema E.g. used clinically for things like brain metastases where there is a lot of oedema

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13
Q

Name an aldosterone analogue.

A

Fludrocortisone

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14
Q

How are all these drugs administered?

A

Orally

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15
Q

Describe the extent of plasma protein binding in each of these four drugs.

A

They bind to plasma proteins – corticosteroid binding globulin + albumin Hydrocortisone is extremely plasma protein bound –90-95% Prednisolone is less bound Dexamethasone and fludrocortisone are even less bound Fludrocortisone only binds to albumin

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16
Q

Where are the corticosteroid drugs metabolised and how are they excreted?

A

Hepatic metabolism Excreted in the bile and urine

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17
Q

Describe the half-lives of the four drugs.

A

In order of increasing half-life (shortest half-life first):  Hydrocortisone + Fludrocortisone (1 hr duration)  Prednisolone (12 hour duration)  Dexamethasone (40 hour duration)

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18
Q

State five reasons for giving corticosteroid replacement therapy

A

Primary adrenocortical failure Secondary adrenocortical failure Acute adrenocortical failure Congenital adrenal hyperplasia Iatrogenic adrenocortical failure

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19
Q

State two causes of primary adrenocortical failure.

A

Addison’s disease Chronic adrenal insufficiency

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20
Q

What is the usual treatment for primary adrenocortical failure?

A

There is a lack of cortisol and aldosterone so you must replace both Hydrocortisone Fludrocortisone

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21
Q

What is secondary adrenocortical failure?

A

The adrenal gland itself is fine but there is a problem with the pituitary gland (ACTH deficiency) There is NORMAL aldosterone production (because aldosterone isn’t dependent on ACTH) So only cortisol needs to be replaced

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22
Q

Describe the treatment of secondary adrenocortical failure.

A

HYDROCORTISONE (titrate the dose to mimic normal physiology)

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23
Q

What is the treatment for acute adrenocortical failure (Addisonian Crisis)?

A

IV saline (because they are suffering from a salt losing crisis) High dose hydrocortisone Dextrose (if they are hypoglycaemic) NOTE: don’t normally need dextrose because the hydrocortisone will increase blood glucose anyway

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24
Q

What is the most common cause of congenital adrenal hyperplasia?

A

21-hydroxylase deficiency

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25
Q

Describe the ACTH levels in CAH and explain the effect this has on steroid synthesis.

A

High ACTH – because no cortisol is being produced so there is no negative feedback on the hypothalamo-pituitary axis High ACTH means that the sex steroid synthesis pathway is turned on – there is an increase in adrenal sex steroids

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26
Q

What are the consequences of CAH in childhood?

A

CAH caused by partial enzyme deficiency can result in virilisation and precocious puberty

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27
Q

How do you treat CAH?

A

Replace cortisol with high dose hydrocortisone (2-3/day) or dexamethasone (1/day) Replace aldosterone with fludrocortisone This is to replace cortisol and to suppress the ACTH axis to reduce adrenal sex steroid production

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28
Q

How do you monitor CAH?

A

Measure 17a-hydroxyprogesterone levels Monitor them clinically – are they complaining of hirsuitism/acne or cushingoid symptoms?

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29
Q

When would you change the dose of hydrocortisone in CAH?

A

If they are under any particular stress such as illness

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30
Q

What is iatrogenic adrenocortical failure?

A

Long-term, high dose glucocorticoid therapy can suppress the HPA axis and hence suppress adrenal function so that they no longer produce cortisol by themselves They need to keep a steroid dependence bracelet

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31
Q

State 4 stimuli for aldosterone release.

A

Angiotensin II High plasma potassium Low plasma sodium Beta-1 stimulation

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32
Q

State some clinical uses of glucocorticoids.

A

Replacement of adrenocortical insufficiency Diagnosis of Cushing’s syndrome (low dose dexamethasone suppression test) Inflammatory disease Hypersensitivity Autoimmune disorders Prevent rejection Neoplastic disease Preterm birth

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33
Q

What is inflammation?

A

Vascular and cellular response to harmful stimuli (it provides powerful defence against pathogens)

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34
Q

State 5 features of inflamed tissue.

A

Red (rubor) Hot (calor) Painful (dolor) Swollen (tumor) Loss of function (function laesa)

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35
Q

What causes these characteristics?

A

Release of inflammatory mediators such as prostaglandins and histamine

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36
Q

Name a type of inflammation of the skin that is a classic reactionto an allergen or injury.

A

Erythema multiforme

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37
Q

What causes this?

A

Histamine release from mast cells

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38
Q

Which types of cells infiltrate tissues in chronic inflammation?

A

Monocytes and lymphocytes

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39
Q

State 4 stimuli for aldosterone release.

A

Angiotensin II High plasma potassium Low plasma sodium Beta-1 stimulation

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40
Q

State 4 main characteristics of the chronic inflammatory response.

A

Tissue damage Local repair Scarring Impaired tissue function

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41
Q

Name a type of ulcer that is caused by chronic inflammation.

A

Pyoderma gangrenosum

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42
Q

What are the two mechanisms of inflammation?

A

Innate  Non-specific  Comprises of vascular and cellular events  Rapid Acquired  Specific

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43
Q

What is the first step of the induction phase of lymphocyte activation?

A

Antigen presentation

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44
Q

Describe this step.

A

Antigen presenting cells pick up antigen and present it on its cell surface Then the APCs are activated and move to the lymph nodes where they encounter CD4+ T cells They have a unique TCR – when it recognises a complementary antigen, it will bind to it (requires costimulation) This binding activates the T-helper cell, which starts to release IL-2

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45
Q

What are the autocrine effects of IL-2 on the T-helper cells?

A

It stimulates the generation of a clone of Th0 cells

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46
Q

Which cytokine stimulates the conversion of Th0 cells to Th1 cells?

A

IL-12

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47
Q

Describe 3 possible outcomes of the Th1 cells.

A

Some will release cytokines that activate macrophages Some will release interferon gamma, which causes differentiation of the Th1 cells into CD8+ T cells –> this develops into cytotoxic T cells Some Th1 become memory cells

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48
Q

Which cytokine is responsible triggers the differentiation of Th0 cells to Th2 cells?

A

IL-4

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49
Q

What effect does the IL-4 released by Th2 cells have on B cells?

A

It stimulates B cell proliferation Some of the clones of B cells will mature into plasma cells that produce antibodies NOTE: in the effector phase of lymphocyte action you get cell-mediated and antibody-mediated actions

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50
Q

Describe the interaction between Th1 and Th2 cells.

A

Th1 produces cytokines that inhibit Th2 cells And Th2 cells produce cytokines that inhibit Th1 cells

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51
Q

State two classes of drugs used to treat inflammation.

A

Non-steroidal anti-inflammatory drugs (e.g. aspirin) Steroidal anti-inflammatory drugs

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52
Q

Describe the effects of glucocorticoids on vascular events

A

Inhibits the vasodilator response Reduced fluid exudation (so reduces redness, swelling, heat and pain)

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53
Q

Describe the effects of glucocorticoids on cellular events.

A

Reduces influx and activity of polymorphonuclear granulocytes Inhibits recruitment and activity of mononuclear cells Inhibits angiogenesis Block clonal proliferation of T cells Inhibit fibroblast function

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54
Q

Which pro-inflammatory mediators do glucocorticoids reduce?

A

Histamine Eicosanoids Complement components Nitric oxide

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55
Q

Describe the effect of glucocorticoids on anti-inflammatory proteins.

A

Enhanced production of anti-inflammatory proteins e.g. annexin-1

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56
Q

What effect do glucocorticoids have on extracellular matrix proteins?

A

Reduced matrix protein production Enhanced production of degrading enzymes

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57
Q

Describe how glucocorticoids have their effects.

A

They pass into the cell through the lipid membrane, bind to the glucocorticoid receptor and the glucocorticoid-receptor complex moves to the nucleus where it influences protein transcription

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58
Q

What are eicosanoids?

A

Metabolites of arachidonic acid

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59
Q

How is arachidonic acid produced?

A

Arachiconic acid is produced from membrane phospholipids by phospholipase A2

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60
Q

Describe how arachidonic acid can be metabolised to produce various important products.

A

Arachidonic acid can be converted by lipoxygenes to leukotrienes and HETEs It can be converted by cyclooxygenase (COX1 and COX2) to endoperoxides (prostacyclin, prostaglandins and thromboxane)

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61
Q

Describe how glucocorticoids inhibit eicosanoid synthesis

A

Glucocorticoids induce synthesis of annexin-1, which then inhibits phospholipase A2 Glucocorticoids also reduce the expression of COX2

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62
Q

Describe how glucocorticoids inhibit the induction and effector phases of lymphocyte activation.

A

They inhibit the expression of cytokine genes (such as IL-2) By inhibiting IL-2, glucocorticoids inhibit the generation of a clone of Th1 cells It also inhibits the activation of macrophages (because macrophages are activated by IL-2 released from Th1 cells) They also have some effect of antibody-mediated reactions because blocking the first IL-2 step will reduce the number of Th0 and, hence, Th2 cells produced –> reduced activation of B-lymphocytes Glucocorticoids target many other cytokines other than IL-2

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63
Q

Name three glucocorticoid drugs.

A

Hydrocortisone Prednisolone Dexamethasone

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64
Q

Why is hydrocortisone generally only used for short-term use?

A

It has quite profound mineralocorticoid effects so has a large side-effect profile when used in high doses

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65
Q

Describe the plasma protein binding of these 3 drugs.

A

Hydrocortisone is the most plasma protein bound (90-95%) – it binds to corticosteroid binding globulin (CBG) and albumin Prednisolone is less plasma protein bound – it binds to CBG Dexamethasone is the least plasma protein bound – it does NOT bind to CBG and binds to albumin weakly NOTE: CBG is also sometimes called transcortin

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66
Q

Describe the metabolism of glucocorticoid drugs.

A

Hepatic metabolism The drug is conjugated and made more water soluble It is excreted in the bile and urine

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67
Q

State the duration of action of the 3 drugs.

A

Hydrocortisone = 8 hours Prednisolone = 12 hours Dexamethasone = 40 hours

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68
Q

State three broad clinical uses of glucocorticoid treatment.

A

Anti-inflammatory and immunosuppressive (e.g. rheumatoid arthritis) Neoplasm (e.g. to reduce cerebral oedema in patients with brain metastases, elevate mood in terminally ill patients, anti-emetic treatment with chemotherapy) Pregnancy – to mature the foetal lung before growth - this reduces the chances of infant respiratory distress syndrome

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69
Q

What is one of the most serious consequences of Cushing’s that is particularly bad in the elderly?

A

Osteoporosis

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70
Q

Describe some ways in which you can minimise the unwanted effects of glucocorticoids.

A

Use locally where possible Intermittent therapy Use glucocorticoid receptor selective glucocorticoids Use minimum effective dose Recommend that patients carry a steroid dependence card

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71
Q

When taking someone off glucocorticoid therapy, why must you withdraw the steroids slowly?

A

Long-term glucocorticoid therapy will suppress the HPA axis and, hence, inhibit ACTH production This leads to adrenal atrophy so the adrenals have lost their capability to respond to stress The dose of glucocorticoids must be reduced slowly to allow time for the adrenals to recover If the glucocorticoids are suddenly withdrawn, it could lead to an adrenal crisis

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72
Q

State some clinical uses of glucocorticoids.

A

Replacement of adrenocortical insufficiency Diagnosis of Cushing’s syndrome (low dose dexamethasone suppression test) Inflammatory disease Hypersensitivity Autoimmune disorders Prevent rejection Neoplastic disease Preterm birth

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73
Q

What is inflammation?

A

Vascular and cellular response to harmful stimuli (it provides powerful defence against pathogens)

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2
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74
Q

State 5 features of inflamed tissue.

A

Red (rubor) Hot (calor) Painful (dolor) Swollen (tumor) Loss of function (function laesa)

How well did you know this?
1
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2
3
4
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75
Q

What causes these characteristics?

A

Release of inflammatory mediators such as prostaglandins and histamine

How well did you know this?
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5
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76
Q

Name a type of inflammation of the skin that is a classic reactionto an allergen or injury.

A

Erythema multiforme

How well did you know this?
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3
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5
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77
Q

What causes this?

A

Histamine release from mast cells

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78
Q

Which types of cells infiltrate tissues in chronic inflammation?

A

Monocytes and lymphocytes

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79
Q

What happens if tissue can’t be repaired completely?

A

Scar tissue is placed instead – this leads to loss of function

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80
Q

State 4 main characteristics of the chronic inflammatory response.

A

Tissue damage Local repair Scarring Impaired tissue function

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81
Q

Name a type of ulcer that is caused by chronic inflammation.

A

Pyoderma gangrenosum

How well did you know this?
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82
Q

What are the two mechanisms of inflammation?

A

Innate  Non-specific  Comprises of vascular and cellular events  Rapid Acquired  Specific

How well did you know this?
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83
Q

What is the first step of the induction phase of lymphocyte activation?

A

Antigen presentation

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84
Q

Describe this step.

A

Antigen presenting cells pick up antigen and present it on its cell surface Then the APCs are activated and move to the lymph nodes where they encounter CD4+ T cells They have a unique TCR – when it recognises a complementary antigen, it will bind to it (requires costimulation) This binding activates the T-helper cell, which starts to release IL-2

How well did you know this?
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85
Q

What are the autocrine effects of IL-2 on the T-helper cells?

A

It stimulates the generation of a clone of Th0 cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
86
Q

Which cytokine stimulates the conversion of Th0 cells to Th1 cells?

A

IL-12

How well did you know this?
1
Not at all
2
3
4
5
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87
Q

Describe 3 possible outcomes of the Th1 cells.

A

Some will release cytokines that activate macrophages Some will release interferon gamma, which causes differentiation of the Th1 cells into CD8+ T cells –> this develops into cytotoxic T cells Some Th1 become memory cells

How well did you know this?
1
Not at all
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88
Q

Which cytokine is responsible triggers the differentiation of Th0 cells to Th2 cells?

A

IL-4

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89
Q

What effect does the IL-4 released by Th2 cells have on B cells?

A

It stimulates B cell proliferation Some of the clones of B cells will mature into plasma cells that produce antibodies NOTE: in the effector phase of lymphocyte action you get cell-mediated and antibody-mediated actions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
90
Q

Describe the interaction between Th1 and Th2 cells.

A

Th1 produces cytokines that inhibit Th2 cells And Th2 cells produce cytokines that inhibit Th1 cells

How well did you know this?
1
Not at all
2
3
4
5
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91
Q

State two classes of drugs used to treat inflammation.

A

Non-steroidal anti-inflammatory drugs (e.g. aspirin) Steroidal anti-inflammatory drugs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
92
Q

Describe the effects of glucocorticoids on vascular events

A

Inhibits the vasodilator response Reduced fluid exudation (so reduces redness, swelling, heat and pain)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
93
Q

Describe the effects of glucocorticoids on cellular events.

A

Reduces influx and activity of polymorphonuclear granulocytes Inhibits recruitment and activity of mononuclear cells Inhibits angiogenesis Block clonal proliferation of T cells Inhibit fibroblast function

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
94
Q

Which pro-inflammatory mediators do glucocorticoids reduce?

A

Histamine Eicosanoids Complement components Nitric oxide

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
95
Q

When taking someone off glucocorticoid therapy, why must you withdraw the steroids slowly?

A

Long-term glucocorticoid therapy will suppress the HPA axis and, hence, inhibit ACTH production This leads to adrenal atrophy so the adrenals have lost their capability to respond to stress The dose of glucocorticoids must be reduced slowly to allow time for the adrenals to recover If the glucocorticoids are suddenly withdrawn, it could lead to an adrenal crisis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
96
Q

Describe some ways in which you can minimise the unwanted effects of glucocorticoids.

A

Use locally where possible Intermittent therapy Use glucocorticoid receptor selective glucocorticoids Use minimum effective dose Recommend that patients carry a steroid dependence card

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
97
Q

What is one of the most serious consequences of Cushing’s that is particularly bad in the elderly?

A

Osteoporosis

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98
Q

State three broad clinical uses of glucocorticoid treatment.

A

Anti-inflammatory and immunosuppressive (e.g. rheumatoid arthritis) Neoplasm (e.g. to reduce cerebral oedema in patients with brain metastases, elevate mood in terminally ill patients, anti-emetic treatment with chemotherapy) Pregnancy – to mature the foetal lung before growth - this reduces the chances of infant respiratory distress syndrome

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1
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99
Q

State the duration of action of the 3 drugs.

A

Hydrocortisone = 8 hours Prednisolone = 12 hours Dexamethasone = 40 hours

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100
Q

Describe the metabolism of glucocorticoid drugs.

A

Hepatic metabolism The drug is conjugated and made more water soluble It is excreted in the bile and urine

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101
Q

Describe the plasma protein binding of these 3 drugs.

A

Hydrocortisone is the most plasma protein bound (90-95%) – it binds to corticosteroid binding globulin (CBG) and albumin Prednisolone is less plasma protein bound – it binds to CBG Dexamethasone is the least plasma protein bound – it does NOT bind to CBG and binds to albumin weakly NOTE: CBG is also sometimes called transcortin

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102
Q

Why is hydrocortisone generally only used for short-term use?

A

It has quite profound mineralocorticoid effects so has a large side-effect profile when used in high doses

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103
Q

Name three glucocorticoid drugs.

A

Hydrocortisone Prednisolone Dexamethasone

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104
Q

Describe how glucocorticoids inhibit the induction and effector phases of lymphocyte activation.

A

They inhibit the expression of cytokine genes (such as IL-2) By inhibiting IL-2, glucocorticoids inhibit the generation of a clone of Th1 cells It also inhibits the activation of macrophages (because macrophages are activated by IL-2 released from Th1 cells) They also have some effect of antibody-mediated reactions because blocking the first IL-2 step will reduce the number of Th0 and, hence, Th2 cells produced –> reduced activation of B-lymphocytes Glucocorticoids target many other cytokines other than IL-2

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105
Q

Describe how glucocorticoids inhibit eicosanoid synthesis

A

Glucocorticoids induce synthesis of annexin-1, which then inhibits phospholipase A2 Glucocorticoids also reduce the expression of COX2

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106
Q

Describe how arachidonic acid can be metabolised to produce various important products.

A

Arachidonic acid can be converted by lipoxygenes to leukotrienes and HETEs It can be converted by cyclooxygenase (COX1 and COX2) to endoperoxides (prostacyclin, prostaglandins and thromboxane)

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107
Q

How is arachidonic acid produced?

A

Arachiconic acid is produced from membrane phospholipids by phospholipase A2

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108
Q

What are eicosanoids?

A

Metabolites of arachidonic acid

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109
Q

Describe how glucocorticoids have their effects.

A

They pass into the cell through the lipid membrane, bind to the glucocorticoid receptor and the glucocorticoid-receptor complex moves to the nucleus where it influences protein transcription

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110
Q

What effect do glucocorticoids have on extracellular matrix proteins?

A

Reduced matrix protein production Enhanced production of degrading enzymes

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111
Q

Describe the effect of glucocorticoids on anti-inflammatory proteins.

A

Enhanced production of anti-inflammatory proteins e.g. annexin-1

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112
Q

What happens if tissue can’t be repaired completely?

A

Scar tissue is placed instead – this leads to loss of function

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113
Q

What are the three major uses of NSAIDs?

A

Anti-pyretic Anti-inflammatory Analgesic

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114
Q

What are most deaths due to NSAIDs caused by?

A

GI ulceration

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115
Q

Broadly speaking, how do NSAIDs act?

A

They inhibit the production of prostanoids by COX enzymes

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116
Q

What are the main prostanoids?

A

Prostaglandins (D2, E2 and F2) Prostacyclin (PGI2) Thromboxane A2

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117
Q

What does COX convert arachidonic acid to?

A

Prostaglandin H2 Which is then converted by specific synthases to:  Thromboxane A2  Prostacyclin (PGI2)  Prostaglandin D2, E2, F2

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118
Q

How are prostanoid receptors named?

A

Prostanoid receptors aren’t very specific - they are named based on which prostanoid they have the highest affinity for (e.g. DP1 has the highest affinity for PGD2)

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119
Q

List all the prostanoid receptors.

A

DP1, DP2 EP1, EP2, EP3, EP4 FP IP1, IP2 TP

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120
Q

What type of receptor are all the prostanoid receptors?

A

G protein coupled receptors (though not all their actions are G protein mediated)

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121
Q

Explain why the EP receptor system is complex.

A

There are four different EP receptors and EP2 has two mechanisms of action and five pathways

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122
Q

State some unwanted actions of PGE2.

A

Increased pain perception Thermoregulation Acute inflammatory response Tumorigenesis Inhibition of apoptosis

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123
Q

How does PGE2 increase pain perception?

A

There is involvement of EP4 receptors and endocannabinoids The mechanism is unclear

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124
Q

How does PGE2 affect body temperature?

A

PGE2 stimulates hypothalamic neurones initiating a rise in body temperature NOTE: there is a bit of a lag between PGE2 rising and temperature rising

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125
Q

Which prostanoid receptor is responsible for signalling in acuteinflammation?

A

EP3 (on mast cells)

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126
Q

Which prostanoid receptor is responsible for the effects of PGE2 on the immune system?

A

EP4

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127
Q

Which diseases are treated with NSAIDs due to its effects on the immune system?

A

Multiple Sclerosis and Rheumatoid Arthritis (Th17 involvement) Contact Dermatitis (Th1 cells involved)

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128
Q

What is the problem with PGE2 inhibiting apoptosis?

A

Inhibition of apoptosis increases the likelihood of necrosis NOTE: there are 3 prostanoids, 7 prostanoid receptors and 2 downstream signalling pathways involved

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129
Q

State some desirable actions of PGE2 and other prostanoids.

A

GASTROPROTECTION Regulation of renal blood flow Bronchodilation Vasoregulation

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130
Q

Describe the gastroprotective action of PGE2.

A

PGE2 downregulates stomach acid production PGE2 stimulates mucus production PGE2 stimulates bicarbonate production

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131
Q

What effect do NSAIDs have on the GI tract?

A

Increased risk of GI ulceration

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132
Q

What main effects does PGE2 have on the kidneys?

A

Increase renal blood flow

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133
Q

What effect do NSAIDs have on the kidneys?

A

Constriction of the afferent arteriole Reduction in renal artery flow Reduced GFR

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134
Q

Why should NSAIDs not be given to asthma patients?

A

Most prostaglandins are bronchodilators, so a reduction in prostaglandin production due to COX inhibition could exacerbate asthma Furthermore, inhibition of COX favours the production of leukotrienes, which are bronchoconstrictors

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135
Q

Prostanoids are vasoregulators, so what are the consequences of NSAIDs on the cardiovascular system?

A

Increased risk of MI and stroke because chronic use of NSAIDs cause:  Small rise in blood pressure  Sodium retention  Vasoconstriction  Can reduce the effectiveness of anti-hypertensives

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136
Q

What is the difference in terms of risk of side effects when using NSAIDs for analgesic use compared to anti-inflammatory use?

A

Analgesic use – usually occasionally used so low risk of side effects Anti-inflammatory use – often sustained use with higher doses = higher risk of side effects

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137
Q

Name two non-selective COX inhibitors.

A

Ibuprofen Indomethacin

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138
Q

Name a COX-2 selective inhibitor.

A

Celecoxib

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139
Q

What is the major problem with COX-2 selective NSAIDs?

A

They have a significantly increased risk of cardiovascular disease than conventional NSAIDs

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140
Q

Describe the relative GI and CVS risks of COX-1 selective and COX-2 selective NSAIDs when compared to non-selective NSAIDs.

A

COX-1 selective:  Same CVS risk as non-selective NSAIDs  Increased GI risk COX-2 selective:  Decreased GI risk  Increased CVS risk

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141
Q

What effect does ibuprofen have on the action of anti-hypertensive drugs?

A

It reduces the effectiveness of anti-hypertensive drugs It will reduce the drop in blood pressure that has been seen when the anti-hypertensives are used without ibuprofen

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142
Q

What are the potential reasons for increased risk of cardiovascular disease with non-selective and COX-2 selective NSAIDs?

A

Non-selective NSAIDs and COX-2 selective NSAIDs both increase cardiac work Also, all NSAIDs produce oxygen free radicals, which can contribute to cardiovascular disease

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143
Q

State some strategies for avoiding/limiting the GI side effects of NSAIDs.

A

Use topical application Minimise NSAID use in patients with a history of GI ulceration Treat H. pylori if present If NSAID is essential, administer omeprazole or another proton pump inhibitor Minimise NSAID use in patients with other risk factors and reduce risk factors where possible e.g. alcohol consumption, anticoagulant use

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144
Q

Describe the action of aspirin.

A

It irreversibly binds to cox enzymes (binds covalently) It is selective for COX-1

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145
Q

Explain how aspirin reduces platelet aggregation.

A

Aspirin irreversibly inhibits COX-1 in platelets meaning that they can’t produce thromboxane A2, which enhances platelet activation and aggregation Furthermore, aspirin preserves the production of prostacyclin, which decreases platelet action

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146
Q

Why is it important to use a low dose of aspirin?

A

A low dose will allow the endothelial cells to resynthesise COX-1, which can then continue to produce prostacyclin A high dose would mean that the COX-1 in the endothelial cells would be inhibited as it is being produced, thus decreasing prostacyclin production as well as thromboxane production

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147
Q

Why don’t you want to inhibit COX-2 too much?

A

Inhibition of prostacyclin synthesis is proportional to inhibition of COX-2 We don’t want to inhibit prostacyclin production too much so we’d like to keep COX-2 inhibition low

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148
Q

What are the major side effects of therapeutic doses of aspirin?

A

Gastric irritation and ulceration Bronchospasm in sensitive asthmatics Prolonged bleeding times Nephrotoxicity

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149
Q

Why is paracetamol NOT an NSAID?

A

It does not have anti-inflammatory action

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150
Q

Explain how paracetamol overdose can cause liver failure.

A

Paracetamol is metabolised to produce a toxic metabolite (N-acetyl-p-benzochinon imine (NAPQI)) This is normally mopped up rapidly by glutathione In overdose, the glutathione stores are depleted and the free toxic metabolite binds indiscriminately to any –SH groups The –SH groups tend to be on key hepatic enzymes and this interference leads to cell death

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151
Q

What is the antidote for paracetamol poisoning?

A

IV Acetyl cysteine This has a lot of –SH groups If this is given too late, the liver damage could be permanent

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152
Q

What legislation was brought in to try and reduce paracetamol related deaths?

A

No more than 2 packs per transaction Illegal to sell more than 100 paracetamol in 1 transaction

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153
Q

Describe the synthesis of acetylcholine.

A

Acetylcholine is synthesised from Acetyl CoA and choline via choline acetyltransferase (CAT)

154
Q

Why are the receptors described as nicotinic and muscarinic?

A

Muscarinic effects are those that can be replicated by muscarine Nicotinic effects are those that an be replicated by nicotine Comes from amanita muscaria and nicotiana tabacum

155
Q

What can be given to abolish muscarinic effects?

A

Atropine (competitive muscarinic antagonist)

156
Q

State where you would find the different types of muscarinic receptor.

A

M1 – salivary glands, CNS, stomach M2 – heart M3 – salivary glands, bronchial/visceral smooth muscle, eyes, and sweat glands M4 and M5 are found in the CNS NOTE: muscarinic receptors are generally excitatory except for on the heart

157
Q

What type of receptor are all muscarinic receptors?

A

G-protein coupled receptors

158
Q

What is the difference in the G-protein receptors of M1, M3 and M5 compared to M2 and M4?

A

M1, M3 and M5 = Gq protein linked receptors – they stimulate PLC which increases IP3 and DAG M2 and M4 = Gi protein linked receptors (inhibitory) – they decrease the production of cAMP

159
Q

Describe the structure of nicotinic receptors. What determines its ligand binding properties?

A

Nicotinic receptors consist of 5 subunits (alpha, beta, gamma, delta or epsilon) The combination of subunits determines its ligand binding properties.

160
Q

What are the two main types of nicotinic receptor? Describe their subunit composition.

A

Muscle and Ganglion Muscle = 2 alpha + beta + delta + epsilon Ganglion = 2 alpha + 3 beta

161
Q

How do the effects of acetylcholine on nicotinic receptors compare to its effects on muscarinic receptors?

A

The effects of acetylcholine are relatively weak on nicotinic compared to muscarinic

162
Q

What three effects does muscarinic stimulation have on the eye?

A

Contraction of the ciliary muscle (accommodate for near vision) Constriction of sphincter pupillae (circular muscle of the eye) – this constricts the pupil and increases drainage of intraocular fluid Lacrimation

163
Q

What is glaucoma?

A

Sustained raised intraocular pressure – this can cause damage to the optic nerves and retina and can lead to blindness

164
Q

Where is aqueous humour produced? Describe its passage through the eye.

A

The capillaries in the ciliary body produce aqueous humour Aqueous humour passes anteriorly into the anterior chamber and is then drained through the canals of Schlemm into the venous system

165
Q

What is the role of aqueous humour?

A

Provides oxygen and nutrients to the cornea and lens because they don’t have a blood supply

166
Q

What happens in Angle-closure glaucoma?

A

The angle between the cornea and the iris is narrowed which decreases the drainage of intraocular fluid through the canals of Schlemm

167
Q

What are the effects of giving a muscarinic agonist to people with Angle-closure glaucoma?

A

This causes constriction of sphincter pupillae and opens up the angle to increase the drainage of intraocular fluid

168
Q

Describe, in detail (including the mechanism), the muscarinic effects on the heart.

A

Binding of acetylcholine to the M2 receptors (Gi protein linked receptor) causes a decrease in cAMP production This triggers a decrease in Ca2+ influx, which leads to a decrease incardiac output It also triggers an increase in K+ efflux, which leads to a decrease in heart rate

169
Q

Describe the muscarinic effects on the vasculature.

A

There is no direct parasympathetic innervation of blood vessels However, there are muscarinic receptors on the endothelial cells When stimulated, it triggers the production of nitric oxide (NO) from the endothelial cells, which causes vasodilation and a decrease in TPR

170
Q

Summarise the muscarinic effects on the cardiovascular system.

A

Decrease in heart rate Decrease in cardiac output (due to decreased atrial contraction) Decrease in total peripheral resistance (due to vasodilation) Decrease in blood pressure

171
Q

Describe the muscarinic effects on non-vascular smooth muscle.

A

It is the opposite of muscarinic effects on vascular smooth muscle It causes CONTRACTION of non-vascular smooth muscle Lungs – bronchoconstriction GI tract – increased motility Bladder – increased bladder emptying

172
Q

Describe the muscarinic effects on exocrine glands.

A

Salivation Increased bronchial secretions Increased GI secretions (including gastric HCl production) Increased sweating (sympathetic-mediated)

173
Q

What are the two types of cholinomimetic drug?

A

Directly Acting – muscarinic agonists Indirectly Acting – acetylcholinesterase inhibitors -> increase the synaptic concentration of acetylcholine

174
Q

State two types of muscarinic receptor agonists and give an example of each.

A

Choline Esters – Bethanechol Alkaloids - Pilocarpine

175
Q

Describe the selectivity of pilocarpine.

A

Non-selective muscarinic receptor agonist It stimulates ALL muscarinic receptors

176
Q

What is pilocarpine used to treat?

A

What is pilocarpine used to treat?

177
Q

State some side-effects of pilocarpine.

A

Blurred vision Hypotension Sweating Respiratory difficulty GI disturbance and pain

178
Q

Describe the selectivity of bethanechol.

A

M3 selective agonist

179
Q

What are the effects of bethanechol?

A

Assist bladder emptying Enhanced gastric motility

180
Q

State some side-effects of bethanechol.

A

Same as pilocarpine + bradycardia, nausea

181
Q

What is the half-life of pilocarpine and bethanechol?

A

3-4 hours

182
Q

What are the two types of anticholinesterase? Give examples of each.

A

Reversible – physostigmine, neostigmine, donepezil Irreversible – ecothiopate, dyflos, sarin

183
Q

What are the two types of cholinesterase?

A

Acetylcholinesterase Butyrylcholinesterase

184
Q

Where is acetylcholinesterase found? Describe its properties.

A

It is found in ALL cholinergic synapses It has very RAPID action and it is HIGHLY SELECTIVE for acetylcholine

185
Q

Where is butyrylcholinesterase found? Describe its properties

A

Butyrylcholinesterase is found in plasma and most tissues but NOT in cholinergic synapses It has a broad substrate specificity – it hydrolyses other esters e.g. suxamethonium It shows genetic variation

186
Q

State the effects of low, moderate and high doses of cholinesterase inhibitors.

A

LOW – enhances muscarinic effects MODERATE – further enhances muscarinic effects + increases transmission at ALL autonomic ganglia (nicotinic receptors) HIGH – depolarising block at autonomic ganglia and NMJ (the nicotinic receptors get overstimulated so they shut down)

187
Q

Describe the mechanism of action of reversible anticholinesterases.

A

Reversible anticholinesterases donate a CARBAMYL group, which blocks the active site of the acetylcholinesterase Carbamyl groups are removed by slow hydrolysis (takes mins rather than miliseconds)

188
Q

Which synapses does pilocarpine primarily act on?

A

Postganglionic parasympathetic synapses

189
Q

What is physostigmine used to treat?

A

Glaucoma

190
Q

What is the half-life of physostigmine?

A

30 mins

191
Q

What type of poisoning is physostigmine used to treat?

A

Atropine poisoning (because it increases the synaptic concentration of acetylcholine so it can outcompete the atropine)

192
Q

What type of compound are irreversible anticholinesterases?

A

Organophosphates

193
Q

Describe the mechanism of action of irreversible anticholinesterases.

A

They rapidly react with the enzyme active site, leaving a large blocking group The blocking group is stable and resistant to hydrolysis so recovery requires the production of new enzymes

194
Q

What is ecothiopate used to treat?

A

Glaucoma

195
Q

State some side-effects of ecothiopate.

A

Blurred vision Sweating Respiratory difficulty Hypotension GI disturbance and pain Bradycardia

196
Q

What type of anticholinesterases can cross the blood-brain barrier?

A

Non-polar

197
Q

Describe the effects of low and high doses of anticholinesterase drugs on CNS activity.

A

Low – CNS excitation with the possibility of convulsions High – unconsciousness, respiratory depression and death

198
Q

State two anticholinesterases that are used to treat Alzheimer’s disease

A

Donepezil Tacrine

199
Q

Describe the treatment of organophosphate poisoning.

A

IV atropine – this blocks the muscarinic receptors thus reducing the effect of the raised synaptic acetylcholine concentration Patient is put on a respiratory because of the respiratory depression caused by the excess acetylcholine at the synapse (causing a depolarising block) If found within the first few hours, the patient should be given IV PRALIDOXIME, which can unblock the enzymes

200
Q

Define Affinity.

A

The strength with which an agonist binds to a receptor

201
Q

Define Efficacy.

A

Once the drug has bound to the receptor, the ability of the drug to transduce a response and activate intracellular signalling pathways is its efficacy

202
Q

Define Affinity.

A

The strength with which an agonist binds to a receptor

203
Q

Define Efficacy.

A

Once the drug has bound to the receptor, the ability of the drug to transduce a response and activate intracellular signalling pathways is its efficacy

204
Q

What is the difference between agonists and antagonists in terms of affinity and efficacy?

A

Agonists – have affinity and efficacy Antagonists – have affinity but NOT efficacy

205
Q

Where are nicotinic receptors found?

A

In ALL autonomic ganglia At neuromuscular junctions

206
Q

Where are muscarinic receptors found?

A

At parasympathetic effector organs and on sweat glands

207
Q

What are the few clinically useful nicotinic receptor antagonists called and how do they block the receptor?

A

Ganglion Blockers These block the ion channel itself, thus preventing the ions from moving through the pore (it doesn’t block the receptor but the channel itself)

208
Q

Give two examples of ganglion blocking drugs.

A

Hexamethonium Trimethaphan

209
Q

What does ‘use-dependent block’ mean?

A

The drugs work most effectively when the ion channels are open. This means that the more agonist is present at the receptor, the opportunity the antagonist has to block the channel, thus the more useful and effective the drugs can be

210
Q

What determines the effect of ganglion blockade in a tissue?

A

It depends on which limb of the autonomic nervous system predominates in the particular tissue (at the time e.g. at rest)

211
Q

Which tissues are sympathetic dominated?

A

Vasculature Kidneys

212
Q

What is the overall effect of ganglion blockade in terms of loss of sympathetic dominance?

A

Hypotension The sympathetic-mediated vasoconstriction is taken away and the ability of the kidneys to increase renin secretion and increase sodium and water reabsorption is also taken away

213
Q

Which tissues are parasympathetic dominated?

A

Lungs – causes bronchoconstriction Eyes – maintains partial pupillary constriction at rest Bladder, ureters and GI tract Exocrine functions

214
Q

What would the effect of ganglion blockage be on these tissues?

A

Bronchodilation Pupil dilation (blurred vision) Bladder dysfunction Loss of GI motility and secretions Decrease in exocrine secretion

215
Q

What is hexamethonium?

A

It is a ganglion blocker that was the first anti-hypertensive It has a generalised action and had loads of side-effects

216
Q

What is trimethaphan and when is it used?

A

The only ganglion-blocking drug that is still in clinical use It is very potent and used when a controlled hypotension is needed in surgery. It is very short acting.

217
Q

In what types of chemicals are nicotinic receptor blockade antagonists found?

A

Toxins and venoms

218
Q

How do receptor blockade antagonists have their effect?

A

These are irreversible – they bind covalently and prevent the ion channels from opening

219
Q

Give an example of a nicotinic receptor blockade antagonist.

A

Alpha-bungarotoxin (common krait snake venom)

220
Q

What are the targets of muscarinic receptor antagonists?

A

Parasympathetic effector organs and sweat glands

221
Q

Give four examples of muscarinic receptor antagonists.

A

Atropine Hyoscine Tropicamide Ipratropium Bromide

222
Q

What effect do muscarinic receptor antagonists have on the CNS?

A

The parasympathetic nervous system is important in the CNS in terms of attention, memory and certain sleep pathways. At low doses atropine can cause mild restlessness At low doses hyoscine can be a good sedative At high doses, both drugs can cause CNS agitation

223
Q

What is tropicamide used for?

A

It is used to dilate the pupil to observe the retina (it is used to examine the eye)

224
Q

What is an important use of muscarinic receptor antagonists with regards to surgery? Why is it useful in this circumstance?

A

Anaesthetic premedication It causes dilation of the airways so it is easier to intubate the patient It reduces secretions thus reducing the risk of aspiration It also knocks out the effect of the parasympathetic nervous system in decreasing heart rate and contractility (because general anaesthetics will decrease heart rate and contractility anyway)

225
Q

What can hyoscine be used to treat? Explain how.

A

Motion Sickness Muscarinic receptors are important in relaying information from the labyrinth in the inner ear to the vomiting centres. Muscarinic receptor antagonists can reduce the flow of information from the labyrinth to the brain thus reducing the nausea.

226
Q

What degenerative disorder of the central nervous system can be treated by muscarinic receptor antagonists? Explain how.

A

Parkinson’s Disease In Parkinson’s disease, many of the nigro-striatal dopamine neurones are lost (these are important in the fine control of movement) Musarinic receptors have a negative effect on this dopamine signalling so by blocking the muscarinic receptors (knocking out the M4 receptors) you can remove this inhibitory effect and allow the remaining dopaminergic neurones to fire at the maximum rate.

227
Q

Explain the use of muscarinic antagonists in treating asthma andCOPD.

A

Ipratropium Bromide is used to treat asthma and COPD It removes the parasympathetic mediated bronchoconstriction

228
Q

Explain the role of muscarinic antagonists in treating irritable bowel syndrome.

A

Muscarinic antagonists will reduce smooth muscle contraction, gut motility and gut secretions thus relieving the symptoms of IBS.

229
Q

State some general unwanted side-effects of muscarinic antagonists.

A

Hot as hell (decreased sweating affects thermoregulation) Dry as bone (due to reduced exocrine secretions) Blind as a bat (due to effects on the accommodation ability of the ciliary muscle – cycloplegia) Mad as a hatter (high doses will cause CNS agitation, restlessness, confusion etc.)

230
Q

How do you treat muscarinic receptor antagonist poisoning (e.g. atropine poisoning)?

A

Give an anticholinesterase e.g. physostigmine

231
Q

Describe how botulinum toxin causes paralysis.

A

It binds to the SNARE complex and prevents the fusion of the vesicles, containing acetylcholine, with the presynaptic membrane thus preventing the release of acetylcholine from the nerve terminal. This leads to muscle paralysis

232
Q

State the overall effects of ganglion blocking drugs on a subject at rest.

A

Hypotension Pupil dilation Bronchodilation Bladder dysfunction Decreased GI tone Decreased GI secretions

233
Q

What is the difference between agonists and antagonists in terms of affinity and efficacy?

A

Agonists – have affinity and efficacy Antagonists – have affinity but NOT efficacy

234
Q

State the overall effects of ganglion blocking drugs on a subject at rest.

A

Hypotension Pupil dilation Bronchodilation Bladder dysfunction Decreased GI tone Decreased GI secretions

235
Q

Describe how botulinum toxin causes paralysis.

A

It binds to the SNARE complex and prevents the fusion of the vesicles, containing acetylcholine, with the presynaptic membrane thus preventing the release of acetylcholine from the nerve terminal. This leads to muscle paralysis

236
Q

How do you treat muscarinic receptor antagonist poisoning (e.g. atropine poisoning)?

A

Give an anticholinesterase e.g. physostigmine

237
Q

State some general unwanted side-effects of muscarinic antagonists.

A

Hot as hell (decreased sweating affects thermoregulation) Dry as bone (due to reduced exocrine secretions) Blind as a bat (due to effects on the accommodation ability of the ciliary muscle – cycloplegia) Mad as a hatter (high doses will cause CNS agitation, restlessness, confusion etc.)

238
Q

Explain the role of muscarinic antagonists in treating irritable bowel syndrome.

A

Muscarinic antagonists will reduce smooth muscle contraction, gut motility and gut secretions thus relieving the symptoms of IBS.

239
Q

Explain the use of muscarinic antagonists in treating asthma andCOPD.

A

Ipratropium Bromide is used to treat asthma and COPD It removes the parasympathetic mediated bronchoconstriction

240
Q

What degenerative disorder of the central nervous system can be treated by muscarinic receptor antagonists? Explain how.

A

Parkinson’s Disease In Parkinson’s disease, many of the nigro-striatal dopamine neurones are lost (these are important in the fine control of movement) Musarinic receptors have a negative effect on this dopamine signalling so by blocking the muscarinic receptors (knocking out the M4 receptors) you can remove this inhibitory effect and allow the remaining dopaminergic neurones to fire at the maximum rate.

241
Q

What can hyoscine be used to treat? Explain how.

A

Motion Sickness Muscarinic receptors are important in relaying information from the labyrinth in the inner ear to the vomiting centres. Muscarinic receptor antagonists can reduce the flow of information from the labyrinth to the brain thus reducing the nausea.

242
Q

What is an important use of muscarinic receptor antagonists with regards to surgery? Why is it useful in this circumstance?

A

Anaesthetic premedication It causes dilation of the airways so it is easier to intubate the patient It reduces secretions thus reducing the risk of aspiration It also knocks out the effect of the parasympathetic nervous system in decreasing heart rate and contractility (because general anaesthetics will decrease heart rate and contractility anyway)

243
Q

What is tropicamide used for?

A

It is used to dilate the pupil to observe the retina (it is used to examine the eye)

244
Q

What effect do muscarinic receptor antagonists have on the CNS?

A

The parasympathetic nervous system is important in the CNS in terms of attention, memory and certain sleep pathways. At low doses atropine can cause mild restlessness At low doses hyoscine can be a good sedative At high doses, both drugs can cause CNS agitation

245
Q

Give four examples of muscarinic receptor antagonists.

A

Atropine Hyoscine Tropicamide Ipratropium Bromide

246
Q

What are the targets of muscarinic receptor antagonists?

A

Parasympathetic effector organs and sweat glands

247
Q

Give an example of a nicotinic receptor blockade antagonist.

A

Alpha-bungarotoxin (common krait snake venom)

248
Q

How do receptor blockade antagonists have their effect?

A

These are irreversible – they bind covalently and prevent the ion channels from opening

249
Q

In what types of chemicals are nicotinic receptor blockade antagonists found?

A

Toxins and venoms

250
Q

What is trimethaphan and when is it used?

A

The only ganglion-blocking drug that is still in clinical use It is very potent and used when a controlled hypotension is needed in surgery. It is very short acting.

251
Q

What is hexamethonium?

A

It is a ganglion blocker that was the first anti-hypertensive It has a generalised action and had loads of side-effects

252
Q

What would the effect of ganglion blockage be on these tissues?

A

Bronchodilation Pupil dilation (blurred vision) Bladder dysfunction Loss of GI motility and secretions Decrease in exocrine secretion

253
Q

Which tissues are parasympathetic dominated?

A

Lungs – causes bronchoconstriction Eyes – maintains partial pupillary constriction at rest Bladder, ureters and GI tract Exocrine functions

254
Q

What is the overall effect of ganglion blockade in terms of loss of sympathetic dominance?

A

Hypotension The sympathetic-mediated vasoconstriction is taken away and the ability of the kidneys to increase renin secretion and increase sodium and water reabsorption is also taken away

255
Q

Which tissues are sympathetic dominated?

A

Vasculature Kidneys

256
Q

What determines the effect of ganglion blockade in a tissue?

A

It depends on which limb of the autonomic nervous system predominates in the particular tissue (at the time e.g. at rest)

257
Q

What does ‘use-dependent block’ mean?

A

The drugs work most effectively when the ion channels are open. This means that the more agonist is present at the receptor, the opportunity the antagonist has to block the channel, thus the more useful and effective the drugs can be

258
Q

Give two examples of ganglion blocking drugs.

A

Hexamethonium Trimethaphan

259
Q

What are the few clinically useful nicotinic receptor antagonists called and how do they block the receptor?

A

Ganglion Blockers These block the ion channel itself, thus preventing the ions from moving through the pore (it doesn’t block the receptor but the channel itself)

260
Q

Where are muscarinic receptors found?

A

At parasympathetic effector organs and on sweat glands

261
Q

Where are nicotinic receptors found?

A

In ALL autonomic ganglia At neuromuscular junctions

262
Q

Describe how impulses are transmitted across synapses.

A

Action potential propagates along the presynaptic neurone -> depolarisation of presynaptic membrane -> opening of voltage gated calcium channels -> calcium influx -> vesicle exocytosis

263
Q

What type of receptor is found at the neuromuscular junction?

A

Nicotinic acetylcholine receptors

264
Q

Where are these receptors found on the muscle fibre?

A

Motor end plate (usually in the middle of the muscle fibres)

265
Q

What does depolarisation of this membrane cause? Describe the character of this depolarisation.

A

This causes a change in end plate potential This is a graded potential meaning that it is dependent on the amount of acetylcholine released and the number of receptors stimulated Once the end plate potential reaches a threshold, it generates an action potential that propagates in both directions along the muscle fibre

266
Q

Where is acetylcholinesterase found?

A

It is bound to the basement membrane in the synaptic cleft

267
Q

State the three main neuromuscule blockers.

A

Tubocurarine Atracurium Suxamethonium

268
Q

State the two main types of nicotinic acetylcholine receptor.

A

Ganglionic Muscle

269
Q

Describe the structure of nicotinic acetylcholine receptors.

A

They consist of 5 subunits (subunits can be alpha, beta, gamma, delta, epsilon) There are always 2 alpha subunits, which bind to acetylcholine and activate the receptor

270
Q

How many molecules of acetylcholine are required to activate one nicotinic acetylcholine receptor?

A

2

271
Q

Name two drugs that are used as spasmolytics and describe theiraction.

A

Diazepam Baclofen (GABA receptor agonist) They both facilitate GABA transmission

272
Q

Give some examples of conditions in which spasmolytics may be used.

A

They are both useful in some forms of cerebral palsy and spasticity following strokes

273
Q

What do local anaesthetics have their effect on?

A

Conduction of action potentials in motor neurones (so if you inject local anaesthetic to a motor neurone then you may see some muscle weakness)

274
Q

Describe the action of neurotoxins.

A

Neurotoxins inhibit the release of acetylcholine and hence block the contraction of respiratory skeletal muscle causing death

275
Q

What are the two types of neuromuscular blocker?

A

Depolarising Non-depolarising

276
Q

Name another spasmolytic that has a different action to create the same effect.

A

Dantrolene – it works in the muscle fibres themselves by inhibiting calcium release in the muscle fibre

277
Q

Describe the difference in mechanism of action between depolarising and non-depolarising NM blockers. Which NM blockers fall into each category?

A

Depolarising = suxamethonium = nicotinic acetylcholine receptor AGONIST Non-depolarising = tubocurarine + atracurium = nicotinic acetylcholine receptor antagonist

278
Q

How do NM blockers affect consciousness and pain sensation?

A

They do NOT

279
Q

What must you always do when giving NM blockers?

A

Assist respiration because of their effect on respiratory muscle action

280
Q

Describe the difference in structure between non-depolarising and depolarising NM blockers?

A

Non-depolarising = big, bulky molecules with limited movement around their bonds Suxamethonium = made up of two acetylcholine molecules that are linked together. This is more flexible and allows rotation. As it is madeup of two acetylcholine molecules it can binds to the two alpha subunits and activate the receptor.

281
Q

Describe the mechanism of action suxamethonium.

A

Suxamethonium is a nicotinic receptor agonist. It causes an extended end plate depolarisation leading to a depolarising block of the NMJ This is a phase 1 block NOTE: it is not metabolised as rapidly as acetylcholine so it will remain bound to the nicotinic receptors making them switch off due to overstimulation It eventually results in FLACCID PARALYSIS

282
Q

What does suxamethonium normally cause before causing the flaccid paralysis?

A

Fasciculations – individual fibre twitches as the suxamethonium begins to stimulate the nicotinic receptor (remember it is an agonist)

283
Q

What is the duration of paralysis of suxamethonium?

A

5 mins

284
Q

How is suxamethonium metabolised?

A

It is metabolised by pseudocholinesterase (butyrylcholinesterase) in the liver and plasma

285
Q

What are some uses of suxamethonium?

A

Endotracheal intubation – relaxes the muscles of the airways Muscle relaxant for electroconvulsive therapy – treatment for severe clinical depression

286
Q

State and explain four unwanted effects of suxamethonium.

A

Post-operative muscle pains  Due to initial fasciculations Hyperkalaemia  If there is soft tissue injury or burns you will lose some neurones innervating the tissuea  Then you will get upregulation of receptors in the skeletal muscle – deinnervation supersensitivity  So if you give suxamethonium you get an exaggerated response with a bigger influx of sodium and bigger efflux of potassium Bradycardia  This is due to the direct muscarinic action on the heart  This effects tends to be prevented because suxamethonium is usually given after GA and hence following administration of atropine (muscarinic antagonist) in the pre-med Raised intraocular pressure  AVOID for eye injuries and glaucoma

287
Q

Describe the mechanism of action of tubocurarine.

A

Tubocurarine is a competitive nicotinic acetylcholine receptor antagonist. You only need 70-80% block to achieve full relaxation of the muscles If you block this proportion of the receptors then the end-plate potential generated will NOT reach the threshold

288
Q

Describe the order of relaxation of skeletal muscles and the orderin which they return back to normal when given tubocurarine.

A

This also causes flaccid paralysis. Order:  Extrinsic eye muscles (first to relax, last to go back to normal)  Small muscles of the face, limbs and pharynx  Respiratory muscles

289
Q

State two uses of tubocurarine.

A

Relaxation of muscles during surgical operations (this means that less general anaesthetic is needed) Permit artificial ventilation

290
Q

How can the actions of NM blockers be reversed?

A

Give an anti-cholinesterase (e.g. physostigmine)

291
Q

What else must you give with this drug when trying to reverse theactions of NM blockers?

A

Atropine Giving physostigmine will raise the synaptic concentration of acetylcholine at ALL cholinergic synapses (not just the neuromuscular junctions) so you need some atropine to block these unwanted effects

292
Q

How are all NM blockers administered?

A

Intravenously

293
Q

What is the duration of paralysis of tubocurarine?

A

40 mins

294
Q

Describe the metabolism and excretion of tubocurarine?

A

It is NOT metabolised at all It is excreted in the urine (70%) and bile (30%)

295
Q

Under which conditions would you get an increased duration of action of tubocurarine? What would you change under these conditions?

A

Impairment of hepatic or renal function increases the duration of action of tubocurarine Under these conditions you would use ATRACURIUM (15 min duration) and is NOT affected by liver or kidney function

296
Q

State some unwanted effects of tubocurarine.

A

MAIN EFFECTS: ganglion block + histamine release from mast cells cause most of the unwanted effects  HYPOTENSION – histamine can act on H1 receptors and cause vasodilation  TACHYCARDIA – reflex tachycardia in response to hypotension  BRONCHOSPASM – caused by histamine release  EXCESSIVE SECRETIONS (bronchial and salivary) – histamine release  APNOEA – which is why you assist respiration

297
Q

State the 5 major classes of anti-emetic drugs.

A

Mixed receptor antagonists Dopamine (D2) receptor antagonists Muscarinic receptor antagonists Serotonin (5-HT3) receptor antagonists Cannabinoids

298
Q

What is nausea and vomiting often preceded by?

A

Sweating, salivation and an increase in heart rate

299
Q

Describe the process of vomiting.

A

Stomach, oesophagus and associated sphincters are relaxed Contraction of upper small intestine, pyloric sphincter and pyloric region of stomach Contents of upper jejunum, duodenum and pyloric region of stomach move to the body and fundus of the stomach Lower and upper oesophageal sphincters and oesophagus relaxes Retching/vomiting may occur

300
Q

What are the consequences of severe vomiting?

A

Dehydration Hypochloraemic metabolic alkalosis Contributes to reduction in bicarbonate excretion and increase in bicarbonate reabsorption Increase in sodium reabsorption and increase in potassium excretion (hypokalaemia)

301
Q

What types of receptors in the stomach transmit signals to the vomiting centre and chemoreceptor trigger zone?

A

Chemoreceptors and Mechanoreceptors

302
Q

What is special about the location of the CTZ and vomiting centre?

A

It is located in a part of the brain that has a very porous blood brain barrier So the CTZ and vomiting centre act as an early warning system to protect the brain from toxin damage

303
Q

Give an example of a mixed receptor antagonist.

A

Promethazine

304
Q

What is this drug a derivative of?

A

Phenothiazine (other phenothiazines are used as neuroleptics)

305
Q

Describe the mode of action of this drug.

A

It is a competitive antagonist for the following receptors:  Histaminergic  Muscarinic  Dopaminergic Order of potency of antagonist activity: H > M > D

306
Q

What are the uses of promethazine?

A

Motion sickness Disorders of the labyrinth Hyperemesis gravidarium Pre and post-operatively Relief of allergic symptoms, anaphylactic emergency, night sedation; insomnia

307
Q

Describe the pharmacokinetics of promethazine.

A

Administer orally Onset of action – 1-2 hours Peak action – 4 hours Duration of action – 24 hours

308
Q

What are the unwanted effects of promethazine?

A

Dizziness Tinnitus Fatigue Sedation Convulsions

309
Q

Give 2 examples of dopamine receptor antagonists.

A

Metoclopramide Domperidone

310
Q

Describe the order of agonist potency of these drugs.

A

D > H > M

311
Q

What effect do these drugs have on the GI tract?

A

They have PROKINETIC effects on the GI tract:  Increase smooth muscle motility  Accelerate gastric emptying  Accelerate the transit time of intestinal contents

312
Q

Why are these drugs poor at treating motion sickness?

A

The vestibular system has connections to the CTZ and it has direct connections to the vomiting centre The dopamine antagonists block dopamine receptors in the CTZ but they are not blocking the rest of the signals that are going directly from the vestibular system to the vomiting centre

313
Q

State some uses of metoclopramide and domperidone.

A

Uraemia (severe renal failure) Radiation sickness GI disorders Cancer chemotherapy

314
Q

Which of these drugs crosses the BBB?

A

Metoclopramide

315
Q

Why must care be given over the bioavailability of co-administered drugs when patients are on dopamine receptor antagonists?

A

These drugs have prokinetic effects on the GI tract hence they accelerate the transit through the GI tract – this may mean that some drugs are not sufficiently absorbed in the GI tract e.g. digoxin

316
Q

What are some unwanted effects of metoclopramide and domperidone?

A

CNS side effects only with metoclopramide:  Drowsiness  Dizziness  Anxiety  Extrapyramidal reactions (Parkinsonian like syndrome – children more susceptible) Endocrine side effects:  Hyperprolactinaemia  Galactorrhoea  Disorders of menstruation

317
Q

Give an example of a muscarinic receptor antagonist.

A

Hyoscine

318
Q

What is the mode of action of muscarinic receptor antagonists?

A

Act centrally on the CTZ, vestibular nuclei and vomiting centre to block the activation of the vomiting centre

319
Q

What is hyoscine used for?

A

Prevention of MOTION SICKNESS Sometimes used in operative pre-medication

320
Q

Describe the pharmacokinetics of hyoscine.

A

Administered orally (peak effect 1-2 hours) Could also be administered via a transdermal skin patch

321
Q

What are the unwanted effects of hyoscine?

A

Drowsiness Dry mouth Cycloplegia Mydriasis Constipation

322
Q

Give an example of a serotonin receptor antagonist.

A

Ondansetron

323
Q

What is the mode of action of serotonin receptor antagonists?

A

Act to block transmission in visceral afferents and CTZ

324
Q

What is the main use of serotonin receptor antagonists as an anti-emetic?

A

MAIN USE: preventing anti-cancer drug induced vomiting (especially cisplatin) Also used for radiotherapy induced sickness and post-operative nausea and vomiting

325
Q

Describe the pharmacokinetics of ondansetron?

A

Adminsitered orally Excreted in urine (good kidney function required)

326
Q

What are the unwanted effects of ondansetron?

A

Headache Sensation of flushing and warmth Constipation

327
Q

Explain the use of combined ondansetron therapy with glucocorticoids.

A

Corticosteroids can be used in combination with ondansetron to treat moderate to high emetogenic chemotherapy The improved efficacy of the combined treatment may be due to the anti-inflammatory properties of corticosteroids

328
Q

What is an opiate?

A

An alkaloid derived form the poppy, Papaver somniferum

329
Q

What are the four most commonly occurring opiates?

A

Morphine Codeine Papaverine Thebaine

330
Q

What is the significance of the tertiary nitrogen in the structure of morphine?

A

It is crucial for receptor anchoring and the analgesic effects of opioids

331
Q

How can the structure of morphine be altered to turn it into anopioid receptor antagonist?

A

The side chain that the tertiary nitrogen is on can be extended by 3+ carbons to turn it into an opioid receptor antagonist

332
Q

What is the importance of the hydroxyl group in position 3 inmorphine?

A

Required for binding

333
Q

How is the structure of codeine different to morphine?

A

Codeine is methyl morphine (methyl group instead of hydroxyl group in position 3)

334
Q

How is the structure of heroin different to morphine?

A

Heroin is diacetyl morphine

335
Q

How does this structural difference affect the properties ofheroin?

A

This means that heroin is much more lipid soluble than morphine so it has much more profound effects on the brain

336
Q

What is a very important feature of methadone and fentanyl?

A

They are extremely lipid soluble

337
Q

Given that opioids are all WEAK BASES, in what state are they likely to be in: a. The stomach b. The small intestine

A

a. The stomach IONISED – relatively little is absorbed b. The small intestine UNIONISED – more readily absorbed

338
Q

In what state will most opioids be in in the blood?

A

Blood has a pH of around 7.4 so the majority of opioids will be ionised in the blood - <20% of opioids will be unionised, and this is thecomponent that can access tissues

339
Q

List morphine, fentanyl, methadone and heroin in order of decreasing lipid solubility.

A

Methadone/fentanyl Heroin Morphine

340
Q

How is the metabolism of morphine different to the metabolism ofother opioids?

A

Morphine is metabolised in the liver and then excreted in the BILE

341
Q

What is the main, active metabolite that is produced from the metabolism of morphine?

A

Morphine-6-glucuronide

342
Q

What happens to this metabolite once it is excreted into the small intestine in the bile?

A

It undergoes enterohepatic cycling and returns to the blood where it can exert its effects

343
Q

Describe the rate of metabolism of fentanyl and methadone.

A

Fentanyl is metabolised rapidly (it can be broken down by cholinesterases in the blood) Methadone is metabolised slowly so remains in the blood for longer

344
Q

What is a use of methadone that is based on its metabolism?

A

It is used to wean people off heroin and morphine – as methadone remains in the blood for longer, it can reduce cravings

345
Q

What percentage of codeine gets converted to morphine?

A

5-10%

346
Q

What are the two enzymes that are involved in codeine metabolism? State their relative rates of action.

A

CYP2D6 – activates codeine to morphine (O-dealkylation) - SLOW CYP3A4 – deactivates codeine - FAST

347
Q

List some endogenous opioid peptides.

A

Endorphins Enkephalins Dynorphins/Neoendorphins

348
Q

Which opioid receptors do the following act on: a. Endorphins b. Enkephalins c. Dynorphins

A

a. Endorphins Mu or Delta b. Enkephalins Delta c. Dynorphins Kappa

349
Q

What are endorphins and enkephalins involved in regulating?

A

Pain/Mood/CNS

350
Q

What are dynorphins involved in regulating?

A

Appetite (hypothalamus)

351
Q

Where in the brain are high concentrations of mu receptors found?

A

Amygdala Nucleus Accumbens Thalamus Periaqueductal Grey matter

352
Q

All opiates are depressants. What are the THREE main mechanisms by which opiates have a depressive effect?

A

Hyperpolarisation (increased K+ efflux) Reduce Ca2+ influx (affects neurotransmitter exocytosis) Reduce adenylate cyclase activity (general reduction in cellular activity)

353
Q

What are the main effects of opioids?

A

Analgesia Euphoria Depression of cough centre Depression of respiratory centre Nausea/Vomiting Pupillary constriction GI effects

354
Q

Broadly speaking, what are the main methods of analgesia?

A

Increase pain tolerance Decrease pain perception

355
Q

Describe the passage of pain information from the stimulus to the thalamus.

A

The painful stimulus is detected by a sensory neurone This then synapses with a spinothalamic neurone in the dorsal horn, which then passes the information to the thalamus

356
Q

What happens as the pain information reaches the thalamus?

A

The thalamus immediately activates the PAG (central pain coordinatingregion of the brain) The thalamus also sends the pain information to the cortex, which processes the pain and modulates the firing of PAG The way in which the cortex affects PAG firing is based on previous experiences, memories etc.

357
Q

What does the PAG do once it has received the input from the thalamus?

A

The PAG activates the nucleus raphe magnus

358
Q

What is the role of NRM?

A

It sends descending inhibitory neurones down to the dorsal horn The NRM is responsible for reducing painful sensation (pain tolerance)

359
Q

What does the NRPG do?

A

NRPG – nucleus reticularis paragigantocellularis It is independent of the thalamus As soon as you sense pain, the NRPG is activated, which then activates NRM You’re trying to suppress pain even before the brain has had a chance to think about it

360
Q

Describe the role of the hypothalamus in this system.

A

The hypothalamus constantly feeds into the PAG about the general health of the organism

361
Q

Describe the role of the Locus Coeruleus in this system.

A

The locus coeruleus is the sympathetic outflow that has a negative effect on pain perception A stress response will activate LC Reason: at a time of stress, you wouldn’t want a painful stimulus to affect your fight or flight response

362
Q

What structure within the spinal cord acts like a ‘mini brain’?

A

Substantia gellatinosa Some of the descending input from the NRM will be processed by the substantia gellatinosa, which then decides the level of inhibition necessary

363
Q

What are the main targets of opioids within this system?

A

Dorsal horn – increase inhibition PAG – enhance PAG firing NRPG – activates this

364
Q

What is the usual mechanism of action of opioids?

A

Inhibition of GABA neurones

365
Q

How do opioids cause euphoria?

A

Opioids bind to mu receptors on GABA neurones and switch them off This removes the inhibitory effect of GABA neurones on the dopaminergic neurones projecting from the ventral tegmental area to the nucleus accumbens –> increase in dopamine release at the nucleus accumbens

366
Q

Describe the central anti-tussive effect of opioids.

A

The 5HT1A receptor in the Dorsal Raphe Nucleus (DRN) is the negative feedback receptor for serotonin – firing of this receptor leads to suppression of serotonin, which leads to activation of the cough centre Opioids desensitise this receptor so serotonin levels rise in the cough centre, which inhibits the motor neurones that connect the cough centre to the larynx

367
Q

What are the two main neurotransmitters released by sensory neurones going from the airways to activate the vagus?

A

Acetylcholine Neurokinin

368
Q

Describe the peripheral anti-tussive effect of opioids.

A

Opioids stop the transmission of information from the sensory nerves tothe vagus

369
Q

What is the most opioid sensitive aspect of respiration?

A

Rhythm generation

370
Q

Which part of the brain is responsible for rhythm generation?

A

Pre-Botzinger complex in the ventrolateral medulla

371
Q

Describe how opioids affect respiration.

A

Opioids inhibit the pre-Botzinger complex They also depress the firing rate of central chemoreceptors, which interferes with the ability of the brain to control respiration

372
Q

How do opioids cause nausea/vomiting?

A

Opioids switch off GABA, which is normally suppressing the chemoreceptor trigger zone This leads to activation of the chemoreceptor trigger zone, which then stimulates vomiting via the medullar vomiting centre

373
Q

Why do opioids cause pinpoint pupils?

A

The preganglionic parasympathetic nerve to the eye is the oculomotor nerve (CN III) This begins in the Edinger-Westphal nucleus There are lots of GABA neurones with mu opioid receptors within the Edinger-Westphal nucleus The removal of the inhibitory GABA input stimulates firing of the oculomotor nerve – MIOSIS

374
Q

What are the effects of opioids on the GI tract?

A

Decrease gastric emptying Decrease GI motility Increase water reabsorption CONSTIPATION NOTE: this is due to the presence of opioid receptors on myenteric neurones

375
Q

Explain how opioids can cause, what looks like, an allergic response?

A

Opioids bind to mast cells in the skin and promote histamine release (skin mast cells appear to be particularly sensitive) The hydroxyl group at position 6 appears to be vital to this

376
Q

What are some symptoms of histamine release?

A

Itching (pruritis) Hives (urticarial) Hypotension

377
Q

What does opioid tolerance tend to be due to?

A

Receptor internalisation

378
Q

Which proteins are important in receptor internalisation?

A

Arrestins

379
Q

Describe opioid withdrawal.

A

Psychological craving Physical withdrawal resembling flu

380
Q

What is thought to be the cause of this powerful withdrawal?

A

One of the mechanisms of action of opioids is to reduce adenylate cyclase activity With long-term use of opioids, the body attempts to compensate by upregulating adenylate cyclase Stopping opioids will result in increased adenylate cyclase activity in tissues –> shakes, headaches, sickness etc.

381
Q

What are some features of opioid overdose?

A

Coma Respiratory depression Pinpoint pupils Hypotension

382
Q

What is the treatment for opioid overdose?

A

Naloxone (IV) This is an opioid receptor antagonist

Imperial (23 decks)

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