54. Asthma & Respiratory Pharmacology Flashcards
(382 cards)
1
Q
A
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
3
Q
What hormone controls the production of adrenal sex steroids?
A
ACTH
4
Q
What controls the production of aldosterone?
A
Angiotensin II
5
Q
State four triggers of aldosterone release
A
Hyperkalaemia Hyponatraemia Drop in renal blood flow Beta-1 stimulation
6
Q
What is the principle action of aldosterone?
A
Increases Na+ reabsorption Increases K+ excretion
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
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
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.
10
Q
Name three glucocorticoid drugs in order of decreasing mineralocorticoid activity.
A
Hydrocortisone (highest mineralocorticoid activity) Prednisolone Dexamethasone
11
Q
What does prednisolone tend to be used for?
A
Immunosuppression
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
13
Q
Name an aldosterone analogue.
A
Fludrocortisone
14
Q
How are all these drugs administered?
A
Orally
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
16
Q
Where are the corticosteroid drugs metabolised and how are they excreted?
A
Hepatic metabolism Excreted in the bile and urine
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)
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
19
Q
State two causes of primary adrenocortical failure.
A
Addison’s disease Chronic adrenal insufficiency
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
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
22
Q
Describe the treatment of secondary adrenocortical failure.
A
HYDROCORTISONE (titrate the dose to mimic normal physiology)
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
24
Q
What is the most common cause of congenital adrenal hyperplasia?
A
21-hydroxylase deficiency
25
Describe the ACTH levels in CAH and explain the effect this has on steroid synthesis.
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
26
What are the consequences of CAH in childhood?
CAH caused by partial enzyme deficiency can result in virilisation and precocious puberty
27
How do you treat CAH?
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
28
How do you monitor CAH?
Measure 17a-hydroxyprogesterone levels Monitor them clinically – are they complaining of hirsuitism/acne or cushingoid symptoms?
29
When would you change the dose of hydrocortisone in CAH?
If they are under any particular stress such as illness
30
What is iatrogenic adrenocortical failure?
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
31
State 4 stimuli for aldosterone release.
Angiotensin II High plasma potassium Low plasma sodium Beta-1 stimulation
32
State some clinical uses of glucocorticoids.
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
33
What is inflammation?
Vascular and cellular response to harmful stimuli (it provides powerful defence against pathogens)
34
State 5 features of inflamed tissue.
Red (rubor) Hot (calor) Painful (dolor) Swollen (tumor) Loss of function (function laesa)
35
What causes these characteristics?
Release of inflammatory mediators such as prostaglandins and histamine
36
Name a type of inflammation of the skin that is a classic reactionto an allergen or injury.
Erythema multiforme
37
What causes this?
Histamine release from mast cells
38
Which types of cells infiltrate tissues in chronic inflammation?
Monocytes and lymphocytes
39
State 4 stimuli for aldosterone release.
Angiotensin II High plasma potassium Low plasma sodium Beta-1 stimulation
40
State 4 main characteristics of the chronic inflammatory response.
Tissue damage Local repair Scarring Impaired tissue function
41
Name a type of ulcer that is caused by chronic inflammation.
Pyoderma gangrenosum
42
What are the two mechanisms of inflammation?
Innate Non-specific Comprises of vascular and cellular events Rapid Acquired Specific
43
What is the first step of the induction phase of lymphocyte activation?
Antigen presentation
44
Describe this step.
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
45
What are the autocrine effects of IL-2 on the T-helper cells?
It stimulates the generation of a clone of Th0 cells
46
Which cytokine stimulates the conversion of Th0 cells to Th1 cells?
IL-12
47
Describe 3 possible outcomes of the Th1 cells.
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
48
Which cytokine is responsible triggers the differentiation of Th0 cells to Th2 cells?
IL-4
49
What effect does the IL-4 released by Th2 cells have on B cells?
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
50
Describe the interaction between Th1 and Th2 cells.
Th1 produces cytokines that inhibit Th2 cells And Th2 cells produce cytokines that inhibit Th1 cells
51
State two classes of drugs used to treat inflammation.
Non-steroidal anti-inflammatory drugs (e.g. aspirin) Steroidal anti-inflammatory drugs
52
Describe the effects of glucocorticoids on vascular events
Inhibits the vasodilator response Reduced fluid exudation (so reduces redness, swelling, heat and pain)
53
Describe the effects of glucocorticoids on cellular events.
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
54
Which pro-inflammatory mediators do glucocorticoids reduce?
Histamine Eicosanoids Complement components Nitric oxide
55
Describe the effect of glucocorticoids on anti-inflammatory proteins.
Enhanced production of anti-inflammatory proteins e.g. annexin-1
56
What effect do glucocorticoids have on extracellular matrix proteins?
Reduced matrix protein production Enhanced production of degrading enzymes
57
Describe how glucocorticoids have their effects.
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
58
What are eicosanoids?
Metabolites of arachidonic acid
59
How is arachidonic acid produced?
Arachiconic acid is produced from membrane phospholipids by phospholipase A2
60
Describe how arachidonic acid can be metabolised to produce various important products.
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)
61
Describe how glucocorticoids inhibit eicosanoid synthesis
Glucocorticoids induce synthesis of annexin-1, which then inhibits phospholipase A2 Glucocorticoids also reduce the expression of COX2
62
Describe how glucocorticoids inhibit the induction and effector phases of lymphocyte activation.
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
63
Name three glucocorticoid drugs.
Hydrocortisone Prednisolone Dexamethasone
64
Why is hydrocortisone generally only used for short-term use?
It has quite profound mineralocorticoid effects so has a large side-effect profile when used in high doses
65
Describe the plasma protein binding of these 3 drugs.
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
66
Describe the metabolism of glucocorticoid drugs.
Hepatic metabolism The drug is conjugated and made more water soluble It is excreted in the bile and urine
67
State the duration of action of the 3 drugs.
Hydrocortisone = 8 hours Prednisolone = 12 hours Dexamethasone = 40 hours
68
State three broad clinical uses of glucocorticoid treatment.
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
69
What is one of the most serious consequences of Cushing’s that is particularly bad in the elderly?
Osteoporosis
70
Describe some ways in which you can minimise the unwanted effects of glucocorticoids.
Use locally where possible Intermittent therapy Use glucocorticoid receptor selective glucocorticoids Use minimum effective dose Recommend that patients carry a steroid dependence card
71
When taking someone off glucocorticoid therapy, why must you withdraw the steroids slowly?
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
72
State some clinical uses of glucocorticoids.
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
73
What is inflammation?
Vascular and cellular response to harmful stimuli (it provides powerful defence against pathogens)
74
State 5 features of inflamed tissue.
Red (rubor) Hot (calor) Painful (dolor) Swollen (tumor) Loss of function (function laesa)
75
What causes these characteristics?
Release of inflammatory mediators such as prostaglandins and histamine
76
Name a type of inflammation of the skin that is a classic reactionto an allergen or injury.
Erythema multiforme
77
What causes this?
Histamine release from mast cells
78
Which types of cells infiltrate tissues in chronic inflammation?
Monocytes and lymphocytes
79
What happens if tissue can’t be repaired completely?
Scar tissue is placed instead – this leads to loss of function
80
State 4 main characteristics of the chronic inflammatory response.
Tissue damage Local repair Scarring Impaired tissue function
81
Name a type of ulcer that is caused by chronic inflammation.
Pyoderma gangrenosum
82
What are the two mechanisms of inflammation?
Innate Non-specific Comprises of vascular and cellular events Rapid Acquired Specific
83
What is the first step of the induction phase of lymphocyte activation?
Antigen presentation
84
Describe this step.
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
85
What are the autocrine effects of IL-2 on the T-helper cells?
It stimulates the generation of a clone of Th0 cells
86
Which cytokine stimulates the conversion of Th0 cells to Th1 cells?
IL-12
87
Describe 3 possible outcomes of the Th1 cells.
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
88
Which cytokine is responsible triggers the differentiation of Th0 cells to Th2 cells?
IL-4
89
What effect does the IL-4 released by Th2 cells have on B cells?
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
90
Describe the interaction between Th1 and Th2 cells.
Th1 produces cytokines that inhibit Th2 cells And Th2 cells produce cytokines that inhibit Th1 cells
91
State two classes of drugs used to treat inflammation.
Non-steroidal anti-inflammatory drugs (e.g. aspirin) Steroidal anti-inflammatory drugs
92
Describe the effects of glucocorticoids on vascular events
Inhibits the vasodilator response Reduced fluid exudation (so reduces redness, swelling, heat and pain)
93
Describe the effects of glucocorticoids on cellular events.
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
94
Which pro-inflammatory mediators do glucocorticoids reduce?
Histamine Eicosanoids Complement components Nitric oxide
95
When taking someone off glucocorticoid therapy, why must you withdraw the steroids slowly?
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
96
Describe some ways in which you can minimise the unwanted effects of glucocorticoids.
Use locally where possible Intermittent therapy Use glucocorticoid receptor selective glucocorticoids Use minimum effective dose Recommend that patients carry a steroid dependence card
97
What is one of the most serious consequences of Cushing’s that is particularly bad in the elderly?
Osteoporosis
98
State three broad clinical uses of glucocorticoid treatment.
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
99
State the duration of action of the 3 drugs.
Hydrocortisone = 8 hours Prednisolone = 12 hours Dexamethasone = 40 hours
100
Describe the metabolism of glucocorticoid drugs.
Hepatic metabolism The drug is conjugated and made more water soluble It is excreted in the bile and urine
101
Describe the plasma protein binding of these 3 drugs.
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
102
Why is hydrocortisone generally only used for short-term use?
It has quite profound mineralocorticoid effects so has a large side-effect profile when used in high doses
103
Name three glucocorticoid drugs.
Hydrocortisone Prednisolone Dexamethasone
104
Describe how glucocorticoids inhibit the induction and effector phases of lymphocyte activation.
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
105
Describe how glucocorticoids inhibit eicosanoid synthesis
Glucocorticoids induce synthesis of annexin-1, which then inhibits phospholipase A2 Glucocorticoids also reduce the expression of COX2
106
Describe how arachidonic acid can be metabolised to produce various important products.
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)
107
How is arachidonic acid produced?
Arachiconic acid is produced from membrane phospholipids by phospholipase A2
108
What are eicosanoids?
Metabolites of arachidonic acid
109
Describe how glucocorticoids have their effects.
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
110
What effect do glucocorticoids have on extracellular matrix proteins?
Reduced matrix protein production Enhanced production of degrading enzymes
111
Describe the effect of glucocorticoids on anti-inflammatory proteins.
Enhanced production of anti-inflammatory proteins e.g. annexin-1
112
What happens if tissue can’t be repaired completely?
Scar tissue is placed instead – this leads to loss of function
113
What are the three major uses of NSAIDs?
Anti-pyretic Anti-inflammatory Analgesic
114
What are most deaths due to NSAIDs caused by?
GI ulceration
115
Broadly speaking, how do NSAIDs act?
They inhibit the production of prostanoids by COX enzymes
116
What are the main prostanoids?
Prostaglandins (D2, E2 and F2) Prostacyclin (PGI2) Thromboxane A2
117
What does COX convert arachidonic acid to?
Prostaglandin H2 Which is then converted by specific synthases to: Thromboxane A2 Prostacyclin (PGI2) Prostaglandin D2, E2, F2
118
How are prostanoid receptors named?
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)
119
List all the prostanoid receptors.
DP1, DP2 EP1, EP2, EP3, EP4 FP IP1, IP2 TP
120
What type of receptor are all the prostanoid receptors?
G protein coupled receptors (though not all their actions are G protein mediated)
121
Explain why the EP receptor system is complex.
There are four different EP receptors and EP2 has two mechanisms of action and five pathways
122
State some unwanted actions of PGE2.
Increased pain perception Thermoregulation Acute inflammatory response Tumorigenesis Inhibition of apoptosis
123
How does PGE2 increase pain perception?
There is involvement of EP4 receptors and endocannabinoids The mechanism is unclear
124
How does PGE2 affect body temperature?
PGE2 stimulates hypothalamic neurones initiating a rise in body temperature NOTE: there is a bit of a lag between PGE2 rising and temperature rising
125
Which prostanoid receptor is responsible for signalling in acuteinflammation?
EP3 (on mast cells)
126
Which prostanoid receptor is responsible for the effects of PGE2 on the immune system?
EP4
127
Which diseases are treated with NSAIDs due to its effects on the immune system?
Multiple Sclerosis and Rheumatoid Arthritis (Th17 involvement) Contact Dermatitis (Th1 cells involved)
128
What is the problem with PGE2 inhibiting apoptosis?
Inhibition of apoptosis increases the likelihood of necrosis NOTE: there are 3 prostanoids, 7 prostanoid receptors and 2 downstream signalling pathways involved
129
State some desirable actions of PGE2 and other prostanoids.
GASTROPROTECTION Regulation of renal blood flow Bronchodilation Vasoregulation
130
Describe the gastroprotective action of PGE2.
PGE2 downregulates stomach acid production PGE2 stimulates mucus production PGE2 stimulates bicarbonate production
131
What effect do NSAIDs have on the GI tract?
Increased risk of GI ulceration
132
What main effects does PGE2 have on the kidneys?
Increase renal blood flow
133
What effect do NSAIDs have on the kidneys?
Constriction of the afferent arteriole Reduction in renal artery flow Reduced GFR
134
Why should NSAIDs not be given to asthma patients?
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
135
Prostanoids are vasoregulators, so what are the consequences of NSAIDs on the cardiovascular system?
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
136
What is the difference in terms of risk of side effects when using NSAIDs for analgesic use compared to anti-inflammatory use?
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
137
Name two non-selective COX inhibitors.
Ibuprofen Indomethacin
138
Name a COX-2 selective inhibitor.
Celecoxib
139
What is the major problem with COX-2 selective NSAIDs?
They have a significantly increased risk of cardiovascular disease than conventional NSAIDs
140
Describe the relative GI and CVS risks of COX-1 selective and COX-2 selective NSAIDs when compared to non-selective NSAIDs.
COX-1 selective: Same CVS risk as non-selective NSAIDs Increased GI risk COX-2 selective: Decreased GI risk Increased CVS risk
141
What effect does ibuprofen have on the action of anti-hypertensive drugs?
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
142
What are the potential reasons for increased risk of cardiovascular disease with non-selective and COX-2 selective NSAIDs?
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
143
State some strategies for avoiding/limiting the GI side effects of NSAIDs.
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
144
Describe the action of aspirin.
It irreversibly binds to cox enzymes (binds covalently) It is selective for COX-1
145
Explain how aspirin reduces platelet aggregation.
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
146
Why is it important to use a low dose of aspirin?
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
147
Why don’t you want to inhibit COX-2 too much?
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
148
What are the major side effects of therapeutic doses of aspirin?
Gastric irritation and ulceration Bronchospasm in sensitive asthmatics Prolonged bleeding times Nephrotoxicity
149
Why is paracetamol NOT an NSAID?
It does not have anti-inflammatory action
150
Explain how paracetamol overdose can cause liver failure.
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
151
What is the antidote for paracetamol poisoning?
IV Acetyl cysteine This has a lot of –SH groups If this is given too late, the liver damage could be permanent
152
What legislation was brought in to try and reduce paracetamol related deaths?
No more than 2 packs per transaction Illegal to sell more than 100 paracetamol in 1 transaction
153
Describe the synthesis of acetylcholine.
Acetylcholine is synthesised from Acetyl CoA and choline via choline acetyltransferase (CAT)
154
Why are the receptors described as nicotinic and muscarinic?
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
What can be given to abolish muscarinic effects?
Atropine (competitive muscarinic antagonist)
156
State where you would find the different types of muscarinic receptor.
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
What type of receptor are all muscarinic receptors?
G-protein coupled receptors
158
What is the difference in the G-protein receptors of M1, M3 and M5 compared to M2 and M4?
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
Describe the structure of nicotinic receptors. What determines its ligand binding properties?
Nicotinic receptors consist of 5 subunits (alpha, beta, gamma, delta or epsilon) The combination of subunits determines its ligand binding properties.
160
What are the two main types of nicotinic receptor? Describe their subunit composition.
Muscle and Ganglion Muscle = 2 alpha + beta + delta + epsilon Ganglion = 2 alpha + 3 beta
161
How do the effects of acetylcholine on nicotinic receptors compare to its effects on muscarinic receptors?
The effects of acetylcholine are relatively weak on nicotinic compared to muscarinic
162
What three effects does muscarinic stimulation have on the eye?
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
What is glaucoma?
Sustained raised intraocular pressure – this can cause damage to the optic nerves and retina and can lead to blindness
164
Where is aqueous humour produced? Describe its passage through the eye.
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
What is the role of aqueous humour?
Provides oxygen and nutrients to the cornea and lens because they don’t have a blood supply
166
What happens in Angle-closure glaucoma?
The angle between the cornea and the iris is narrowed which decreases the drainage of intraocular fluid through the canals of Schlemm
167
What are the effects of giving a muscarinic agonist to people with Angle-closure glaucoma?
This causes constriction of sphincter pupillae and opens up the angle to increase the drainage of intraocular fluid
168
Describe, in detail (including the mechanism), the muscarinic effects on the heart.
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
Describe the muscarinic effects on the vasculature.
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
Summarise the muscarinic effects on the cardiovascular system.
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
Describe the muscarinic effects on non-vascular smooth muscle.
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
Describe the muscarinic effects on exocrine glands.
Salivation Increased bronchial secretions Increased GI secretions (including gastric HCl production) Increased sweating (sympathetic-mediated)
173
What are the two types of cholinomimetic drug?
Directly Acting – muscarinic agonists Indirectly Acting – acetylcholinesterase inhibitors -\> increase the synaptic concentration of acetylcholine
174
State two types of muscarinic receptor agonists and give an example of each.
Choline Esters – Bethanechol Alkaloids - Pilocarpine
175
Describe the selectivity of pilocarpine.
Non-selective muscarinic receptor agonist It stimulates ALL muscarinic receptors
176
What is pilocarpine used to treat?
What is pilocarpine used to treat?
177
State some side-effects of pilocarpine.
Blurred vision Hypotension Sweating Respiratory difficulty GI disturbance and pain
178
Describe the selectivity of bethanechol.
M3 selective agonist
179
What are the effects of bethanechol?
Assist bladder emptying Enhanced gastric motility
180
State some side-effects of bethanechol.
Same as pilocarpine + bradycardia, nausea
181
What is the half-life of pilocarpine and bethanechol?
3-4 hours
182
What are the two types of anticholinesterase? Give examples of each.
Reversible – physostigmine, neostigmine, donepezil Irreversible – ecothiopate, dyflos, sarin
183
What are the two types of cholinesterase?
Acetylcholinesterase Butyrylcholinesterase
184
Where is acetylcholinesterase found? Describe its properties.
It is found in ALL cholinergic synapses It has very RAPID action and it is HIGHLY SELECTIVE for acetylcholine
185
Where is butyrylcholinesterase found? Describe its properties
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
State the effects of low, moderate and high doses of cholinesterase inhibitors.
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
Describe the mechanism of action of reversible anticholinesterases.
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
Which synapses does pilocarpine primarily act on?
Postganglionic parasympathetic synapses
189
What is physostigmine used to treat?
Glaucoma
190
What is the half-life of physostigmine?
30 mins
191
What type of poisoning is physostigmine used to treat?
Atropine poisoning (because it increases the synaptic concentration of acetylcholine so it can outcompete the atropine)
192
What type of compound are irreversible anticholinesterases?
Organophosphates
193
Describe the mechanism of action of irreversible anticholinesterases.
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
What is ecothiopate used to treat?
Glaucoma
195
State some side-effects of ecothiopate.
Blurred vision Sweating Respiratory difficulty Hypotension GI disturbance and pain Bradycardia
196
What type of anticholinesterases can cross the blood-brain barrier?
Non-polar
197
Describe the effects of low and high doses of anticholinesterase drugs on CNS activity.
Low – CNS excitation with the possibility of convulsions High – unconsciousness, respiratory depression and death
198
State two anticholinesterases that are used to treat Alzheimer’s disease
Donepezil Tacrine
199
Describe the treatment of organophosphate poisoning.
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
Define Affinity.
The strength with which an agonist binds to a receptor
201
Define Efficacy.
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
Define Affinity.
The strength with which an agonist binds to a receptor
203
Define Efficacy.
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
What is the difference between agonists and antagonists in terms of affinity and efficacy?
Agonists – have affinity and efficacy Antagonists – have affinity but NOT efficacy
205
Where are nicotinic receptors found?
In ALL autonomic ganglia At neuromuscular junctions
206
Where are muscarinic receptors found?
At parasympathetic effector organs and on sweat glands
207
What are the few clinically useful nicotinic receptor antagonists called and how do they block the receptor?
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
Give two examples of ganglion blocking drugs.
Hexamethonium Trimethaphan
209
What does ‘use-dependent block’ mean?
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
What determines the effect of ganglion blockade in a tissue?
It depends on which limb of the autonomic nervous system predominates in the particular tissue (at the time e.g. at rest)
211
Which tissues are sympathetic dominated?
Vasculature Kidneys
212
What is the overall effect of ganglion blockade in terms of loss of sympathetic dominance?
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
Which tissues are parasympathetic dominated?
Lungs – causes bronchoconstriction Eyes – maintains partial pupillary constriction at rest Bladder, ureters and GI tract Exocrine functions
214
What would the effect of ganglion blockage be on these tissues?
Bronchodilation Pupil dilation (blurred vision) Bladder dysfunction Loss of GI motility and secretions Decrease in exocrine secretion
215
What is hexamethonium?
It is a ganglion blocker that was the first anti-hypertensive It has a generalised action and had loads of side-effects
216
What is trimethaphan and when is it used?
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
In what types of chemicals are nicotinic receptor blockade antagonists found?
Toxins and venoms
218
How do receptor blockade antagonists have their effect?
These are irreversible – they bind covalently and prevent the ion channels from opening
219
Give an example of a nicotinic receptor blockade antagonist.
Alpha-bungarotoxin (common krait snake venom)
220
What are the targets of muscarinic receptor antagonists?
Parasympathetic effector organs and sweat glands
221
Give four examples of muscarinic receptor antagonists.
Atropine Hyoscine Tropicamide Ipratropium Bromide
222
What effect do muscarinic receptor antagonists have on the CNS?
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
What is tropicamide used for?
It is used to dilate the pupil to observe the retina (it is used to examine the eye)
224
What is an important use of muscarinic receptor antagonists with regards to surgery? Why is it useful in this circumstance?
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
What can hyoscine be used to treat? Explain how.
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
What degenerative disorder of the central nervous system can be treated by muscarinic receptor antagonists? Explain how.
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
Explain the use of muscarinic antagonists in treating asthma andCOPD.
Ipratropium Bromide is used to treat asthma and COPD It removes the parasympathetic mediated bronchoconstriction
228
Explain the role of muscarinic antagonists in treating irritable bowel syndrome.
Muscarinic antagonists will reduce smooth muscle contraction, gut motility and gut secretions thus relieving the symptoms of IBS.
229
State some general unwanted side-effects of muscarinic antagonists.
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
How do you treat muscarinic receptor antagonist poisoning (e.g. atropine poisoning)?
Give an anticholinesterase e.g. physostigmine
231
Describe how botulinum toxin causes paralysis.
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
State the overall effects of ganglion blocking drugs on a subject at rest.
Hypotension Pupil dilation Bronchodilation Bladder dysfunction Decreased GI tone Decreased GI secretions
233
What is the difference between agonists and antagonists in terms of affinity and efficacy?
Agonists – have affinity and efficacy Antagonists – have affinity but NOT efficacy
234
State the overall effects of ganglion blocking drugs on a subject at rest.
Hypotension Pupil dilation Bronchodilation Bladder dysfunction Decreased GI tone Decreased GI secretions
235
Describe how botulinum toxin causes paralysis.
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
How do you treat muscarinic receptor antagonist poisoning (e.g. atropine poisoning)?
Give an anticholinesterase e.g. physostigmine
237
State some general unwanted side-effects of muscarinic antagonists.
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
Explain the role of muscarinic antagonists in treating irritable bowel syndrome.
Muscarinic antagonists will reduce smooth muscle contraction, gut motility and gut secretions thus relieving the symptoms of IBS.
239
Explain the use of muscarinic antagonists in treating asthma andCOPD.
Ipratropium Bromide is used to treat asthma and COPD It removes the parasympathetic mediated bronchoconstriction
240
What degenerative disorder of the central nervous system can be treated by muscarinic receptor antagonists? Explain how.
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
What can hyoscine be used to treat? Explain how.
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
What is an important use of muscarinic receptor antagonists with regards to surgery? Why is it useful in this circumstance?
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
What is tropicamide used for?
It is used to dilate the pupil to observe the retina (it is used to examine the eye)
244
What effect do muscarinic receptor antagonists have on the CNS?
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
Give four examples of muscarinic receptor antagonists.
Atropine Hyoscine Tropicamide Ipratropium Bromide
246
What are the targets of muscarinic receptor antagonists?
Parasympathetic effector organs and sweat glands
247
Give an example of a nicotinic receptor blockade antagonist.
Alpha-bungarotoxin (common krait snake venom)
248
How do receptor blockade antagonists have their effect?
These are irreversible – they bind covalently and prevent the ion channels from opening
249
In what types of chemicals are nicotinic receptor blockade antagonists found?
Toxins and venoms
250
What is trimethaphan and when is it used?
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
What is hexamethonium?
It is a ganglion blocker that was the first anti-hypertensive It has a generalised action and had loads of side-effects
252
What would the effect of ganglion blockage be on these tissues?
Bronchodilation Pupil dilation (blurred vision) Bladder dysfunction Loss of GI motility and secretions Decrease in exocrine secretion
253
Which tissues are parasympathetic dominated?
Lungs – causes bronchoconstriction Eyes – maintains partial pupillary constriction at rest Bladder, ureters and GI tract Exocrine functions
254
What is the overall effect of ganglion blockade in terms of loss of sympathetic dominance?
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
Which tissues are sympathetic dominated?
Vasculature Kidneys
256
What determines the effect of ganglion blockade in a tissue?
It depends on which limb of the autonomic nervous system predominates in the particular tissue (at the time e.g. at rest)
257
What does ‘use-dependent block’ mean?
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
Give two examples of ganglion blocking drugs.
Hexamethonium Trimethaphan
259
What are the few clinically useful nicotinic receptor antagonists called and how do they block the receptor?
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
Where are muscarinic receptors found?
At parasympathetic effector organs and on sweat glands
261
Where are nicotinic receptors found?
In ALL autonomic ganglia At neuromuscular junctions
262
Describe how impulses are transmitted across synapses.
Action potential propagates along the presynaptic neurone -\> depolarisation of presynaptic membrane -\> opening of voltage gated calcium channels -\> calcium influx -\> vesicle exocytosis
263
What type of receptor is found at the neuromuscular junction?
Nicotinic acetylcholine receptors
264
Where are these receptors found on the muscle fibre?
Motor end plate (usually in the middle of the muscle fibres)
265
What does depolarisation of this membrane cause? Describe the character of this depolarisation.
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
Where is acetylcholinesterase found?
It is bound to the basement membrane in the synaptic cleft
267
State the three main neuromuscule blockers.
Tubocurarine Atracurium Suxamethonium
268
State the two main types of nicotinic acetylcholine receptor.
Ganglionic Muscle
269
Describe the structure of nicotinic acetylcholine receptors.
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
How many molecules of acetylcholine are required to activate one nicotinic acetylcholine receptor?
2
271
Name two drugs that are used as spasmolytics and describe theiraction.
Diazepam Baclofen (GABA receptor agonist) They both facilitate GABA transmission
272
Give some examples of conditions in which spasmolytics may be used.
They are both useful in some forms of cerebral palsy and spasticity following strokes
273
What do local anaesthetics have their effect on?
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
Describe the action of neurotoxins.
Neurotoxins inhibit the release of acetylcholine and hence block the contraction of respiratory skeletal muscle causing death
275
What are the two types of neuromuscular blocker?
Depolarising Non-depolarising
276
Name another spasmolytic that has a different action to create the same effect.
Dantrolene – it works in the muscle fibres themselves by inhibiting calcium release in the muscle fibre
277
Describe the difference in mechanism of action between depolarising and non-depolarising NM blockers. Which NM blockers fall into each category?
Depolarising = suxamethonium = nicotinic acetylcholine receptor AGONIST Non-depolarising = tubocurarine + atracurium = nicotinic acetylcholine receptor antagonist
278
How do NM blockers affect consciousness and pain sensation?
They do NOT
279
What must you always do when giving NM blockers?
Assist respiration because of their effect on respiratory muscle action
280
Describe the difference in structure between non-depolarising and depolarising NM blockers?
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
Describe the mechanism of action suxamethonium.
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
What does suxamethonium normally cause before causing the flaccid paralysis?
Fasciculations – individual fibre twitches as the suxamethonium begins to stimulate the nicotinic receptor (remember it is an agonist)
283
What is the duration of paralysis of suxamethonium?
5 mins
284
How is suxamethonium metabolised?
It is metabolised by pseudocholinesterase (butyrylcholinesterase) in the liver and plasma
285
What are some uses of suxamethonium?
Endotracheal intubation – relaxes the muscles of the airways Muscle relaxant for electroconvulsive therapy – treatment for severe clinical depression
286
State and explain four unwanted effects of suxamethonium.
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
Describe the mechanism of action of tubocurarine.
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
Describe the order of relaxation of skeletal muscles and the orderin which they return back to normal when given tubocurarine.
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
State two uses of tubocurarine.
Relaxation of muscles during surgical operations (this means that less general anaesthetic is needed) Permit artificial ventilation
290
How can the actions of NM blockers be reversed?
Give an anti-cholinesterase (e.g. physostigmine)
291
What else must you give with this drug when trying to reverse theactions of NM blockers?
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
How are all NM blockers administered?
Intravenously
293
What is the duration of paralysis of tubocurarine?
40 mins
294
Describe the metabolism and excretion of tubocurarine?
It is NOT metabolised at all It is excreted in the urine (70%) and bile (30%)
295
Under which conditions would you get an increased duration of action of tubocurarine? What would you change under these conditions?
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
State some unwanted effects of tubocurarine.
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
State the 5 major classes of anti-emetic drugs.
Mixed receptor antagonists Dopamine (D2) receptor antagonists Muscarinic receptor antagonists Serotonin (5-HT3) receptor antagonists Cannabinoids
298
What is nausea and vomiting often preceded by?
Sweating, salivation and an increase in heart rate
299
Describe the process of vomiting.
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
What are the consequences of severe vomiting?
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
What types of receptors in the stomach transmit signals to the vomiting centre and chemoreceptor trigger zone?
Chemoreceptors and Mechanoreceptors
302
What is special about the location of the CTZ and vomiting centre?
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
Give an example of a mixed receptor antagonist.
Promethazine
304
What is this drug a derivative of?
Phenothiazine (other phenothiazines are used as neuroleptics)
305
Describe the mode of action of this drug.
It is a competitive antagonist for the following receptors: Histaminergic Muscarinic Dopaminergic Order of potency of antagonist activity: H \> M \> D
306
What are the uses of promethazine?
Motion sickness Disorders of the labyrinth Hyperemesis gravidarium Pre and post-operatively Relief of allergic symptoms, anaphylactic emergency, night sedation; insomnia
307
Describe the pharmacokinetics of promethazine.
Administer orally Onset of action – 1-2 hours Peak action – 4 hours Duration of action – 24 hours
308
What are the unwanted effects of promethazine?
Dizziness Tinnitus Fatigue Sedation Convulsions
309
Give 2 examples of dopamine receptor antagonists.
Metoclopramide Domperidone
310
Describe the order of agonist potency of these drugs.
D \> H \> M
311
What effect do these drugs have on the GI tract?
They have PROKINETIC effects on the GI tract: Increase smooth muscle motility Accelerate gastric emptying Accelerate the transit time of intestinal contents
312
Why are these drugs poor at treating motion sickness?
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
State some uses of metoclopramide and domperidone.
Uraemia (severe renal failure) Radiation sickness GI disorders Cancer chemotherapy
314
Which of these drugs crosses the BBB?
Metoclopramide
315
Why must care be given over the bioavailability of co-administered drugs when patients are on dopamine receptor antagonists?
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
What are some unwanted effects of metoclopramide and domperidone?
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
Give an example of a muscarinic receptor antagonist.
Hyoscine
318
What is the mode of action of muscarinic receptor antagonists?
Act centrally on the CTZ, vestibular nuclei and vomiting centre to block the activation of the vomiting centre
319
What is hyoscine used for?
Prevention of MOTION SICKNESS Sometimes used in operative pre-medication
320
Describe the pharmacokinetics of hyoscine.
Administered orally (peak effect 1-2 hours) Could also be administered via a transdermal skin patch
321
What are the unwanted effects of hyoscine?
Drowsiness Dry mouth Cycloplegia Mydriasis Constipation
322
Give an example of a serotonin receptor antagonist.
Ondansetron
323
What is the mode of action of serotonin receptor antagonists?
Act to block transmission in visceral afferents and CTZ
324
What is the main use of serotonin receptor antagonists as an anti-emetic?
MAIN USE: preventing anti-cancer drug induced vomiting (especially cisplatin) Also used for radiotherapy induced sickness and post-operative nausea and vomiting
325
Describe the pharmacokinetics of ondansetron?
Adminsitered orally Excreted in urine (good kidney function required)
326
What are the unwanted effects of ondansetron?
Headache Sensation of flushing and warmth Constipation
327
Explain the use of combined ondansetron therapy with glucocorticoids.
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
What is an opiate?
An alkaloid derived form the poppy, Papaver somniferum
329
What are the four most commonly occurring opiates?
Morphine Codeine Papaverine Thebaine
330
What is the significance of the tertiary nitrogen in the structure of morphine?
It is crucial for receptor anchoring and the analgesic effects of opioids
331
How can the structure of morphine be altered to turn it into anopioid receptor antagonist?
The side chain that the tertiary nitrogen is on can be extended by 3+ carbons to turn it into an opioid receptor antagonist
332
What is the importance of the hydroxyl group in position 3 inmorphine?
Required for binding
333
How is the structure of codeine different to morphine?
Codeine is methyl morphine (methyl group instead of hydroxyl group in position 3)
334
How is the structure of heroin different to morphine?
Heroin is diacetyl morphine
335
How does this structural difference affect the properties ofheroin?
This means that heroin is much more lipid soluble than morphine so it has much more profound effects on the brain
336
What is a very important feature of methadone and fentanyl?
They are extremely lipid soluble
337
Given that opioids are all WEAK BASES, in what state are they likely to be in: a. The stomach b. The small intestine
a. The stomach IONISED – relatively little is absorbed b. The small intestine UNIONISED – more readily absorbed
338
In what state will most opioids be in in the blood?
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
List morphine, fentanyl, methadone and heroin in order of decreasing lipid solubility.
Methadone/fentanyl Heroin Morphine
340
How is the metabolism of morphine different to the metabolism ofother opioids?
Morphine is metabolised in the liver and then excreted in the BILE
341
What is the main, active metabolite that is produced from the metabolism of morphine?
Morphine-6-glucuronide
342
What happens to this metabolite once it is excreted into the small intestine in the bile?
It undergoes enterohepatic cycling and returns to the blood where it can exert its effects
343
Describe the rate of metabolism of fentanyl and methadone.
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
What is a use of methadone that is based on its metabolism?
It is used to wean people off heroin and morphine – as methadone remains in the blood for longer, it can reduce cravings
345
What percentage of codeine gets converted to morphine?
5-10%
346
What are the two enzymes that are involved in codeine metabolism? State their relative rates of action.
CYP2D6 – activates codeine to morphine (O-dealkylation) - SLOW CYP3A4 – deactivates codeine - FAST
347
List some endogenous opioid peptides.
Endorphins Enkephalins Dynorphins/Neoendorphins
348
Which opioid receptors do the following act on: a. Endorphins b. Enkephalins c. Dynorphins
a. Endorphins Mu or Delta b. Enkephalins Delta c. Dynorphins Kappa
349
What are endorphins and enkephalins involved in regulating?
Pain/Mood/CNS
350
What are dynorphins involved in regulating?
Appetite (hypothalamus)
351
Where in the brain are high concentrations of mu receptors found?
Amygdala Nucleus Accumbens Thalamus Periaqueductal Grey matter
352
All opiates are depressants. What are the THREE main mechanisms by which opiates have a depressive effect?
Hyperpolarisation (increased K+ efflux) Reduce Ca2+ influx (affects neurotransmitter exocytosis) Reduce adenylate cyclase activity (general reduction in cellular activity)
353
What are the main effects of opioids?
Analgesia Euphoria Depression of cough centre Depression of respiratory centre Nausea/Vomiting Pupillary constriction GI effects
354
Broadly speaking, what are the main methods of analgesia?
Increase pain tolerance Decrease pain perception
355
Describe the passage of pain information from the stimulus to the thalamus.
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
What happens as the pain information reaches the thalamus?
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
What does the PAG do once it has received the input from the thalamus?
The PAG activates the nucleus raphe magnus
358
What is the role of NRM?
It sends descending inhibitory neurones down to the dorsal horn The NRM is responsible for reducing painful sensation (pain tolerance)
359
What does the NRPG do?
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
Describe the role of the hypothalamus in this system.
The hypothalamus constantly feeds into the PAG about the general health of the organism
361
Describe the role of the Locus Coeruleus in this system.
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
What structure within the spinal cord acts like a ‘mini brain’?
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
What are the main targets of opioids within this system?
Dorsal horn – increase inhibition PAG – enhance PAG firing NRPG – activates this
364
What is the usual mechanism of action of opioids?
Inhibition of GABA neurones
365
How do opioids cause euphoria?
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
Describe the central anti-tussive effect of opioids.
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
What are the two main neurotransmitters released by sensory neurones going from the airways to activate the vagus?
Acetylcholine Neurokinin
368
Describe the peripheral anti-tussive effect of opioids.
Opioids stop the transmission of information from the sensory nerves tothe vagus
369
What is the most opioid sensitive aspect of respiration?
Rhythm generation
370
Which part of the brain is responsible for rhythm generation?
Pre-Botzinger complex in the ventrolateral medulla
371
Describe how opioids affect respiration.
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
How do opioids cause nausea/vomiting?
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
Why do opioids cause pinpoint pupils?
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
What are the effects of opioids on the GI tract?
Decrease gastric emptying Decrease GI motility Increase water reabsorption CONSTIPATION NOTE: this is due to the presence of opioid receptors on myenteric neurones
375
Explain how opioids can cause, what looks like, an allergic response?
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
What are some symptoms of histamine release?
Itching (pruritis) Hives (urticarial) Hypotension
377
What does opioid tolerance tend to be due to?
Receptor internalisation
378
Which proteins are important in receptor internalisation?
Arrestins
379
Describe opioid withdrawal.
Psychological craving Physical withdrawal resembling flu
380
What is thought to be the cause of this powerful withdrawal?
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
What are some features of opioid overdose?
Coma Respiratory depression Pinpoint pupils Hypotension
382
What is the treatment for opioid overdose?
Naloxone (IV) This is an opioid receptor antagonist
