52. Hypertension & Cardiac Failure 💦 Flashcards
(195 cards)
1
Q
A
2
Q
What is the major store of calcium within the cardiomyocyte?
A
Sarcoplasmic reticulum
3
Q
The heart has two signalling pathways that are involved in elevating the level of two intracellular second messengers. What are these second messengers?
A
Ca2+ and cAMP
4
Q
Which plasma membrane proteins allow calcium to enter the cell in response to depolarisation?
A
Dihydropyridine receptors
5
Q
What happens to the calcium once it has passes into the cell viathis channel?
A
It binds to ryanodine receptors on the sarcoplasmic reticulum and cause calcium release from the SR
6
Q
How does the calcium stimulate contraction?
A
It binds to troponin on the thin filament
7
Q
What are the different ways in which calcium is removed from the myoplasm after it has stimulated contraction? Which method is responsible for the majority of calcium removal?
A
Plasma membrane calcium ATPase Na+/Ca2+ exchanger SERCA2a (sarcoendoplasmic reticulum calcium ATPase) –responsible for >70% of calcium removal
8
Q
What features of contraction is SERCA2a responsible for andwhy?
A
Rate of calcium removal and so it’s responsible for the rate of cardiac muscle relaxation Size of calcium store, which affects the contractility of the subsequent beat
9
Q
What regulates the action of SERCA2a and how does it do this?
A
Phospholamban (PLN) Phospholamban phosphorylation is stimulated by beta-adrenergic activity It is a target for phosphorylation by protein kinase A When dephosphorylated it is an inhibitor of SERCA2a When phosphorylated it dissociates from SERCA2a and activates the Ca2+ pump As a result, the rate of cardiac relaxation is increased and, on subsequent beats, contractility is in proportion to the elevation in the size of the SR calcium store
10
Q
What is phospholamban dephosphorylated by?
A
Protein phosphatase 1
11
Q
What are the three main channels that are responsible for the action potential in the sinoatrial node?
A
If channel – hyperpolarisation-activated cyclic nucleotide-gated (HCN) channel Calcium channel (T and L type) Potassium channel
12
Q
Describe how these channels are responsible for the action potential of the sinoatrial node.
A
If channel is a sodium channel that opens at the most negative membrane potential Opening of the sodium channel causes sodium influx, which begins to depolarise the membrane and stimulates the opening of calcium channels, which further depolarises the membrane Potassium channels are responsible for repolarisation
13
Q
What are beta adrenoceptors coupled with?
A
Adenylate cyclase – it increases cAMP, which is important in the opening of the If channel to begin depolarisation
14
Q
How does the parasympathetic nervous system affect heart rate and contractility?
A
It is negatively coupled with adenylate cyclase
15
Q
What are the determinants of myocardial oxygen supply?
A
Arterial oxygen content Coronary blood flow
16
Q
What are the determinents of myocardial oxygen demand?
A
Heart rate Contractility Preload Afterload
17
Q
What effect do beta-blockers and calcium channel blockers haveon the channels responsible for the SA node action potential?
A
Beta-blockers decrease If and calcium channel activity Calcium channel blockers only decrease calcium channel activity
18
Q
Name a drug that decreases If activity.
A
Ivabradine (blocks the If channel)
19
Q
What effect does this drug have on contractility?
A
It has no effect on contractility because it doesn’t affect the calcium channels
20
Q
What are the two types of calcium channel blocker? Name the drugs in each category including their drug class.
A
Rate slowing Phenylalkylamines – verapamil Benzothiazepines – diltiazem Non-rate slowing Dihydropyridines – amlodipine
21
Q
What is a consequence of non-rate slowing calcium channel blockers?
A
Reflex tachycardia (baroreceptor reflex)
22
Q
How do organic nitrates cause vasodilation?
A
Organic nitrates are substrates for nitric oxide production The NO then diffuses into the smooth muscle and causes smooth muscle relaxation by activating guanylate cyclase They are often in angina patients before they exercise
23
Q
How do potassium channel openers work?
A
They open the potassium channels and hyperpolarise the vascular smooth muscle so that it is less likely to contract
24
Q
How do vasodilation and venodilation reduce myocardial oxygen demand?
A
They reduce the pressure against which the heart is pumping (reduce afterload) and it also causes reduce venous return to the heart (reduced preload) meaning that contractility is decreased
25
As these drugs reduce the myocardial oxygen demand, what condition can they all be used to treat?
Angina pectoris
26
State some unwanted effects of beta-blockers.
Bradycardia Hypotension Hypoglycaemia in diabetics on insulin Cold extremities (because of beta-2 blockade) Bronchoconstriction Fatigue Impotence Depression CNS effects
27
Under what circumstance must caution be taken when giving beta-blockers?
Cardiac failure – because they reduce heart rate and contractility it can have catastrophic consequences in cardiac failure patients
28
What are the side effects of verapamil?
Bradycardia and AV block Constipation
29
What are the side effects of dihydropyridines?
Ankle oedema Headaches/flushing Palpitations
30
What is a simple classification of arrhythmias?
Based on its point of origin Supraventricular, Ventricular and Complex
31
What is the main classification of anti-arrhythmic drugs and how are the drugs ordered?
Vaughan-Williams classification I – sodium channel blockers II – beta-blockers III – prolongation of repolarisation (mainly due to potassium channelblockade) IV – calcium channel blockers
32
What is adenosine used to treat?
It is used to terminate supraventricular tachycardia
33
How does adenosine work?
Adenosine binds to adenosine receptors in the cardiac muscle and vascular smooth muscle Adenosine receptors are negatively coupled with adenylate cyclase Reducing the cAMP in nodal tissue will impact on depolarisation within the AV node
34
What is verapamil used to treat?
Supraventricular tachycardia Atrial fibrillation
35
What is the target of verapamil and how does it work?
L-type calcium channel Reducing calcium entry means that the speed with which the tissue is depolarise is reduced
36
What is amiodarone used to treat?
Supraventricular tachyarrhythmia Ventricular tachyarrhythmia
37
How does amiodarone work?
It works by blocking many ion channels Its main effect seems to be through potassium channel blockade This prolongs repolarisation, so you’re prolonging the time during which the tissue can’t depolarise
38
Describe re-entry.
Some damaged cardiac tissue will make it difficult for depolarisation to pass through it in one direction, but it will allow the action potential to propagate in the opposite direction This could mean that you get a miniature circuit set up within the tissueand you get re-entry of action potentials
39
What is the target of cardiac glycosides like digoxin?
Na+/K+ ATPase
40
How does digoxin work and what are its effects on the heart?
By blocking Na+/K+ ATPase it causes an accumulation of Na+ in the cell The excess Na+ is then removed by Na+/Ca2+ exchanger, thus increasing the intracellular calcium concentration This has an inotropic effect It also causes vagal stimulation, which has a chronotropic effect
41
What is an important factor to consider before starting treatment with digoxin?
Hypokalaemia Digoxin binds to the potassium binding site on the extracellular component of Na+/K+ ATPase so it competes with potassium for the binding site If hypokalaemic, there is less competition for digoxin and so the effects of digoxin are exaggerated
42
What is digoxin used to treat?
Atrial fibrillation Atrial flutter
43
What is an adverse effect of digoxin?
Dysrrhythmia
44
What are cardiac inotropes? Name two.
They increase the contractility of the heart (it is used in acute heart failure in some cases) Dobutamine (beta-1 agonist) Milrinone (phosphodiesterase inhibitor)
45
Name three drug classes that interfere with the renin-angiotensin system.
Renin inhibitors ACE inhibitors Angiotensin receptor blockers
46
Describe the action of aldosterone in collecting duct tubule cells.
Aldosterone passes through the plasma membrane and binds to mineralocorticoid receptors intracellularly and increases the synthesis of Na+ channels and Na+/K+ pumps This causes an increase in sodium reabsorption
47
What are the uses of ACE inhibitors?
Hypertension Heart Failure Diabetic Nephropathy Post-MI Progressive Renal Insufficiency Patients at high risk of cerebrovascular disease
48
Give an example of an ACE inhibitor.
Enalapril
49
What are the anti-hypertensive effects of ACE inhibitors?
They reduce the production of angiotensin II, which is a potent vasoconstrictor It also reduces the production of aldosterone, thus reducing salt and water retention This means that there is a decrease in blood volume, hence a decrease in venous return
50
What law links venous return to contractility?
Starling’s Law
51
What is diabetic nephropathy caused by?
It is due to significant damage to the kidney glomerulus because of toxic products NOTE: hyperglycaemia increases the risk of exposure to oxygen free radicals
52
Name three drug classes that interfere with the renin-angiotensin system.
Renin inhibitors ACE inhibitors Angiotensin receptor blockers
53
Describe the action of aldosterone in collecting duct tubule cells.
Aldosterone passes through the plasma membrane and binds to mineralocorticoid receptors intracellularly and increases the synthesis of Na+ channels and Na+/K+ pumps This causes an increase in sodium reabsorption
54
What are the uses of ACE inhibitors?
Hypertension Heart Failure Diabetic Nephropathy Post-MI Progressive Renal Insufficiency Patients at high risk of cerebrovascular disease
55
Give an example of an ACE inhibitor.
Enalapril
56
What are the anti-hypertensive effects of ACE inhibitors?
They reduce the production of angiotensin II, which is a potent vasoconstrictor It also reduces the production of aldosterone, thus reducing salt and water retention This means that there is a decrease in blood volume, hence a decrease in venous return
57
What law links venous return to contractility?
Starling’s Law
58
What is diabetic nephropathy caused by?
It is due to significant damage to the kidney glomerulus because of toxic products NOTE: hyperglycaemia increases the risk of exposure to oxygen free radicals
59
Why are ACE inhibitors used in diabetic nephropathy?
ACE inhibitors reduce the angiotensin II-mediated vasoconstriction of the efferent arteriole This reduces the blood pressure at the glomerulus and hence reduces the accumulation of toxic products at the glomerulus
60
Give an example of an angiotensin receptor blocker.
Losartan
61
What is the most common side effect of ACE inhibitors?
COUGH
62
State some other side effects of ACE inhibitors and ARBs.
Hypotension Urticaria/Angioedema (ACEi – very rare) Hyperkalaemia Fetal injury Renal failure in patients with renal artery stenosis (due to both)
63
Describe the excitation-contraction coupling of vascular smooth muscle cells.
Deplarisation causes the opening of voltage-gated calcium channels (VGCC) This leads to calcium influx The calcium then binds to calmodulin forming a Ca2+-CaM complex This complex activates Myosin Light Chain Kinase (MLCK), and the MLCK-mediated phosphorylation leads to smooth muscle contraction
64
What type of calcium channel blocker is more selective for blood vessels? Give an example.
Dihydropyridines – nicardipine
65
Give two examples of non-rate slowing CCBs.
Nicardipine Nitrendipine Amlodipine Nisoldipine
66
Which part of the calcium channel do the different CCBs bind to?
Dihydropyridines bind to the extracellularly component of the calcium channel Diltiazem and verapamil binds to the intracellular component so for a CCB to have an effect on the heart it needs to be able to penetrate the membrane and act on the receptor inside the cell
67
Why are non-rate slowing CCBs preferred to rate-slowing CCBs in the treatment of hypertension and heart failure?
They have a more powerful effect on vascular smooth muscle
68
What type of receptor is a beta adrenoceptor?
G-protein coupled receptor (Gs protein linked)
69
What are the effects of noradrenaline that cause an increase in blood pressure?
Increase in heart rate and cardiac contractility (leads to increase in CO) via beta-1 receptors in the heart Stimulation of beta-1 receptors in the kidneys promotes renin release --\> increase in angiotensin II
70
What is hypertension in younger patients normally caused by?
Increased sympathetic drive
71
State some uses of beta-blockers.
Angina Post-MI Cardiac dysrhythmias Chronic heart failure Hypertension Also thyrotoxicosis, glaucoma, anxiety states, migraine prophylaxis, benign essential tremor
72
Give an example of a cardio-selective beta-blocker.
Atenolol
73
What are mixed beta-alpha blockers? Give an example.
They are beta-1, beta-2 and alpha-1 blockers Carvedilol You get extra vasodilation due to alpha-1 blockade
74
Give an example of an alpha-1 blocker.
Prazosin
75
Give an example of a non-selective alpha blocker.
Phentolamine
76
Why is it important for alpha-1 blockers to be selective?
Alpha-2 receptors are the negative feedback receptors of the SNS Blocking them will result in enhancement of sympathetic activity
77
Give an example of a drug that is used to treat migraine and explain how it works.
Sumatriptan It is a 5-HT (serotonin) receptor agonist, which causes vasoconstriction of some of the large arteries in the brain and inhibits trigeminal nerve transmission NOTE: painful stimuli is transferred by the trigeminal nerve and profound vasodilation is also associated with migraine
78
When is sumatriptan contraindicated?
Coronary disease
79
What are the side effects of sumatriptan?
Dizziness, drowsiness, asthenia/fatigue
80
What is step 1 in the NICE guidelines for treatment of hypertension?
\< 55 years = ACEi + ARB \>55 years or Afro-Caribbean of any age = CCBs + thiazide-type diuretics
81
What is step 2?
ACEi or ARB AND CCB or thiazide diuretic
82
What is step 3?
ACEi/ARB CCB Thiazide diuretic
83
What is step 4?
Further diuretic therapy (low-dose spironolactone) Alpha or beta-blocker
84
What is spironolactone?
It is an aldosterone receptor antagonist
85
What is chronic heart failure?
Impaired cardiac function due to ischaemic heart disease, hypertension or cardiomyopathy that results in fluid retention, oedema and fatigue
86
Which drugs are normally used on patients with chronic heart failure?
ACEi ARB Beta-blockers Spironolactone
87
Why are ACE inhibitors used in diabetic nephropathy?
ACE inhibitors reduce the angiotensin II-mediated vasoconstriction of the efferent arteriole This reduces the blood pressure at the glomerulus and hence reduces the accumulation of toxic products at the glomerulus
88
Which drugs are normally used on patients with chronic heart failure?
ACEi ARB Beta-blockers Spironolactone
89
What is chronic heart failure?
Impaired cardiac function due to ischaemic heart disease, hypertension or cardiomyopathy that results in fluid retention, oedema and fatigue
90
What is spironolactone?
It is an aldosterone receptor antagonist
91
What is step 4?
Further diuretic therapy (low-dose spironolactone) Alpha or beta-blocker
92
What is step 3?
ACEi/ARB CCB Thiazide diuretic
93
What is step 2?
ACEi or ARB AND CCB or thiazide diuretic
94
What is step 1 in the NICE guidelines for treatment of hypertension?
\< 55 years = ACEi + ARB \>55 years or Afro-Caribbean of any age = CCBs + thiazide-type diuretics
95
What are the side effects of sumatriptan?
Dizziness, drowsiness, asthenia/fatigue
96
When is sumatriptan contraindicated?
Coronary disease
97
Give an example of a drug that is used to treat migraine and explain how it works.
Sumatriptan It is a 5-HT (serotonin) receptor agonist, which causes vasoconstriction of some of the large arteries in the brain and inhibits trigeminal nerve transmission NOTE: painful stimuli is transferred by the trigeminal nerve and profound vasodilation is also associated with migraine
98
Why is it important for alpha-1 blockers to be selective?
Alpha-2 receptors are the negative feedback receptors of the SNS Blocking them will result in enhancement of sympathetic activity
99
Give an example of a non-selective alpha blocker.
Phentolamine
100
Give an example of an alpha-1 blocker.
Prazosin
101
What are mixed beta-alpha blockers? Give an example.
They are beta-1, beta-2 and alpha-1 blockers Carvedilol You get extra vasodilation due to alpha-1 blockade
102
Give an example of a cardio-selective beta-blocker.
Atenolol
103
State some uses of beta-blockers.
Angina Post-MI Cardiac dysrhythmias Chronic heart failure Hypertension Also thyrotoxicosis, glaucoma, anxiety states, migraine prophylaxis, benign essential tremor
104
What is hypertension in younger patients normally caused by?
Increased sympathetic drive
105
What are the effects of noradrenaline that cause an increase in blood pressure?
Increase in heart rate and cardiac contractility (leads to increase in CO) via beta-1 receptors in the heart Stimulation of beta-1 receptors in the kidneys promotes renin release --\> increase in angiotensin II
106
What type of receptor is a beta adrenoceptor?
G-protein coupled receptor (Gs protein linked)
107
Why are non-rate slowing CCBs preferred to rate-slowing CCBs in the treatment of hypertension and heart failure?
They have a more powerful effect on vascular smooth muscle
108
Which part of the calcium channel do the different CCBs bind to?
Dihydropyridines bind to the extracellularly component of the calcium channel Diltiazem and verapamil binds to the intracellular component so for a CCB to have an effect on the heart it needs to be able to penetrate the membrane and act on the receptor inside the cell
109
Give two examples of non-rate slowing CCBs.
Nicardipine Nitrendipine Amlodipine Nisoldipine
110
What type of calcium channel blocker is more selective for blood vessels? Give an example.
Dihydropyridines – nicardipine
111
Describe the excitation-contraction coupling of vascular smooth muscle cells.
Deplarisation causes the opening of voltage-gated calcium channels (VGCC) This leads to calcium influx The calcium then binds to calmodulin forming a Ca2+-CaM complex This complex activates Myosin Light Chain Kinase (MLCK), and the MLCK-mediated phosphorylation leads to smooth muscle contraction
112
State some other side effects of ACE inhibitors and ARBs.
Hypotension Urticaria/Angioedema (ACEi – very rare) Hyperkalaemia Fetal injury Renal failure in patients with renal artery stenosis (due to both)
113
What is the most common side effect of ACE inhibitors?
COUGH
114
Give an example of an angiotensin receptor blocker.
Losartan
115
Describe the effects of each type of adrenoceptor. Alpha 1 Alpha 2 Beta 1 Beta 2 Beta 3
Alpha 1  Vasoconstriction  GI tract relaxation Alpha 2  Inhibition of transmitter release  Contraction of vascular smooth muscle  CNS actions Beta 1  Heart – increased heart rate + contractility  Kidneys – increased renin release  GI tract relaxation Beta 2  Bronchodilation  Vasodilation  Relaxation of visceral smooth muscle  Hepatic glycogenolysis Beta 3  Lipolysis
116
State five adrenoceptor antagonists including the receptors that they block.
Labetalol = alpha 1 + beta 1 (more beta 1 (4:1)) Phentolamine = alpha 1 + alpha 2 Prazosin = alpha 1 Propranolol = beta 1 + beta 2 Atenolol = beta 1
117
State four main clinical uses of SNS antagonists and false transmitters.
Hypertension Angina Arrhythmia Glaucoma
118
What is defined as hypertension?
Sustained diastolic blood pressure greater than 90 mm Hg
119
State three elements that contribute to hypertension.
Blood volume Peripheral vascular tone Cardiac output
120
What is the main control of blood pressure?
Sympathetic drive to the kidneys via beta 1 receptors This triggers renin release from the kidneys (leads to an increase in angiotensin II and aldosterone)
121
Blockade of which receptors cause the positive effects and thenegative effects of beta-blockers?
Beta 1 blockade = positive effects Beta 2 blockade = negative effects
122
What are beta-1 selective blockers called?
Cardioselective Beta-blockers
123
What effect is responsible for most of the anti-hypertensive effect of beta-blockers?
Beta 1 blockade in the kidneys – this reduces renin release from the kidneys
124
What effect does beta-1 blockade have on the heart?
Decrease in heart rate Decrease in cardiac output
125
How does the effect of beta-blockers on the heart change?
The effect of beta blockade on the heart disappears with chronic treatment as the heart begins to reset itself
126
What is the effect of presynaptic beta 1 receptors?
They have a positive facilitation effect on the synthesis and release of neurotransmitter
127
State four conditions in which you would not give a patient a betablocker. Explain each of them.
Asthma – blockade of beta 2 receptors in the lungs can take away the beta 2 mediated bronchodilation, which can be fatal in asthmatics Cardiac Failure – these patients rely on a certain degree of sympathetic drive to the heart to maintain adequate cardiac output COPD – same reason as asthma Diabetes – beta blockade masks the symptoms of hypoglycaemia (e.g. tremors, palpitations, sweating) and beta 2 blockade also inhibits hepatic glycogenolysis
128
State some other unwanted actions of beta-blockers.
Fatigue Cold extremities
129
What effect does propranolol have on heart rate, cardiac output and blood pressure?
It has little effect on these parameters at rest It decreases all of these parameters when exercising
130
Why would you still not give a cardioselective beta-blocker to anasthmatic patient?
Selectivity is dependent on concentration
131
What are the effects of labetalol?
Acts more on beta 1 than alpha 1 It lowers blood pressure by reducing total peripheral resistance and it induces a change in heart rate and cardiac output (beta 1 mediated)
132
What is the main mediator of total peripheral resistance?
Alpha 1 mediated vasoconstriction
133
What are the effects of alpha blockade?
Vasodilation causing a fall in TPR and hence a fall in blood pressure NOTE: blocking the sympathetic drive can cause postural hypotension
134
What reflex will be triggered by alpha blockade?
It triggers a baroreceptor mediated reflex tachycardia to increase heart rate and cardiac output
135
State some of the problems with non-selective alpha blockers (e.g. phentolamine).
Alpha 1 blockade will cause vasodilation and a fall in TPR and blood pressure But the alpha 2 blockade will mean that you take away the negative effect of alpha 2 on the synthesis and release of noradrenaline so more noradrenaline will be released from the nerve terminal This enhances the reflex tachycardia Side effects include increased GIT motility and diarrhoea Phentolamine is no longer used
136
What are the effects of prazosin?
Highly selective alpha-1 antagonist Leads to vasodilation and a fall in blood pressure You get less tachycardia than with non-selective alpha blockers because the negative effect of alpha 2 on noradrenaline release has not been removed NOTE: postural hypotension is troublesome Prazosin also increases HDL and decreases LDL so is becoming more popular as an anti-hypertensive
137
Describe the mechanism of action of methyldopa.
Methyldopa is taken up by noradrenergic neurones and is decarboxylated and hydroxylated for form alpha-methyl noradrenaline This is not deaminated by MAO so accumulates more than noradrenaline in the synapse Alpha-methyl noradrenaline displaces NA from the synaptic vesicles It is less effective than NA on alpha 1 receptors so does not cause as much vasoconstriction It is more effective than NA on alpha 2 receptors thus reducing noradrenaline release It also affects the CNS by inhibiting sympathetic outflow
138
State some other benefits of methyldopa other than its effect as an anti-hypertensive.
It does not have any adverse effects on foetus’ despite crossing the placenta It maintains renal and CNS blood flow so it is used in patients with renal insufficiency or cerebrovascular disease Adverse effects: dry mouth, sedation, postural hypotension, male sexual dysfunction It is RARELY used
139
What are arrhythmias usually caused by and why?
Myocardial ischaemia – damage to the heart muscle can result in re-entry of impulses that messes up the heart rhythm
140
What controls the pacemaker current in the heart?
Sympathetic drive
141
What can precipitate or aggravate arrhythmias?
An increase in sympathetic drive to the heart via beta 1 receptors
142
What part of the heart’s electrical circuit depends heavily on sympathetic activity?
AV conductance depends heavily on sympathetic activity
143
What effect do beta antagonists have on the refractory period of the AV node? How does this help in dealing with arrhythmia?
Beta-blockers INCREASE the refractory period of the AV node It can interfere with AV conduction in atrial tachycardias and slow downventricular rate
144
What class of drugs are beta-blockers?
Class II anti-arrhythmics
145
What is propranolol particularly effective at treating?
It is particularly successful in arrhythmias that occur during exercise or mental stress
146
Define angina.
Chest pain that occurs when the oxygen supply to the myocardium is insufficient for its needs
147
Describe the three different types of angina.
Stable ï‚· Pain on exertion due to a FIXED narrowing Unstable ï‚· Pain with less and less exertion culminating with pain at rest ï‚· Atheromatous plaque begins to rupture ï‚· Platelet-fibrin thrombus associated with the ruptured plaque without complete occlusion of the vessel ï‚· High risk of infarction Variable ï‚· Occurs at rest ï‚· Caused by coronary artery spasm ï‚· Associated with atheromatous disease
148
Describe how beta-blockers can help prevent angina attacks.
They decrease heart rate, decrease contractility and decrease systolic blood pressure meaning that it will reduce the oxygen demand of the heart whilst maintaining the same degree of effort This means that you are less likely of getting to a situation where theoxygen supply to the myocardium is insufficient for its needs (angina)
149
State some adverse effects of beta-blockers.
Fatigue Insomnia Dizziness Sexual dysfunction Bronchospasm Bradycardia Heart block Hypotension Decreased myocardial contractility
150
State some other circumstances in which you would not give a beta-blocker.
Hypotension Bradycardia Bronchospasm AV block or severe congestive heart failure
151
Where is aqueous humour produced?
They are produced by the blood vessels in the ciliary body via the actions of carbonic anhydrase
152
What dictates the amount of aqueous humour produced?
Blood flow in the ciliary body (and blood pressure)
153
Where does the aqueous humour drain?
It drains into the trabecular meshwork in the canals of Schlemm
154
How can adrenaline affect intraocular pressure?
Adrenaine can act on alpha-1 receptors to cause vasoconstriction and reduce blood flow through the ciliary body
155
Describe the use of beta antagonists in treating glaucoma.
They reduce the rate of aqueous humour formation by blocking the receptors on the ciliary body Examples: carteolol hydrochloride, levobunolol hydrochloride, timilol maleate
156
State some other uses of beta antagonists.
Anxiety states (to control somatic symptoms associated with sympathetic ove reactivity such as palpitations and tremor) Migraine prophylaxis – maintain good blood supply within the CNS so reduces the risk of migraines Benign essential tumour
157
From which region of the spinal cord do sympathetic fibres originate?
Thoracolumbar
158
Most sympathetic post-ganglionic neurones release noradrenaline. State two exceptions.
Adrenal medulla – adrenaline (80%) and noradrenaline (20%) Sweat glands – acetylcholine
159
State the difference between directly and indirectly acting sympathomimetics.
Directly acting – binds to the adrenoceptor and mimic the action of adrenaline and noradrenaline by stimulating the receptors Indirectly acting – inhibits the uptake and breakdown systems leading to the accumulation of neurotransmitter in the synaptic cleft
160
Describe the mechanism of action of the four different types of adrenoceptor.
ALL adrenoceptors are G-protein coupled Alpha 1 = PLC -\> IP3 + DAG Alpha 2 = decrease cAMP Beta 1 + Beta 2 = increase cAMP
161
State the main actions of beta-1 receptors.
HEART – increase heart rate + increase contractility KIDNEYS – increase renin release -\> increase blood pressure Lipolysis
162
State the main actions of beta-2 receptors.
Bronchodilation Hepatic glucose output – glycogenolysis + gluconeogenesis Vasodilation of vessels to skeletal muscle Relaxation of the uterus (in women)
163
State some effects that are mediated by both alpha and beta-receptors.
Exocrine secretions (e.g. salivary gland secretions become thick) GIT motility – decreased muscle motility and tone + contraction of sphincters
164
What receptors are responsible for the production of aqueoushumour by the ciliary body?
Beta receptors
165
State some effects of alpha-1 receptors.
Mydriasis (contraction of radial muscles of the iris) Vasoconstriction Constriction of trigone and sphincter in the bladder Increased motility and tone of the ureters Stimulates ejaculation (in males) Lacrimation Contraction of pilomotor muscle + increased localised secretion of sweat glands e.g. palm of hands Hepatic glucose output (glycogenolysis and gluconeogenesis) Lipolysis
166
What is the principle action of beta-blockers?
KIDNEYS – it inhibits the beta-1 mediated increase in renin secretion It also decreases heart rate and contractility but its main action in reducing blood pressure is through the kidneys
167
Describe the relative selectivity of adrenaline and noradrenaline.
Noradrenaline is more selective for ALPHA-receptors Adrenaline is more selective for BETA-receptors
168
Describe the action of pre-synaptic alpha-2 receptors.
Pre-synaptic alpha-2 receptors have a negative influence on noradrenaline synthesis and release
169
State five directly acting SNS agonists.
Phenylephrine – alpha-1 Clonidine – alpha-2 Dobutamine – beta-1 Salbutamol – beta-2 Isoprenaline – beta 1+ beta 2
170
Describe the development of hypersensitivity following first exposure.
After the first exposure you generate antibodies to the antigen andthese circulate around the body and bind to mast cells. In the subsequent exposure, the mast cells are primed with the antibody on its surface. Cross-linking of these antibodies on the surface of mast cells causes massive release of the stored mediators leading to the symptoms of hypersensitivity.
171
State some symptoms of hypersensitivity.
Increase in capillary permeability leads to increased movement of fluid into the tissues. This depletes the circulating fluid volume leading to adrop in blood pressure -\> ANAPHYLACTIC SHOCK (and collapse the circulatory system leading to unconsciousness) This can also lead to contraction of bronchial smooth muscle and constriction of muscles around the throat causing respiratory distress. It can also constrict GI smooth muscle causing vomiting and diarrhoea.
172
Why is adrenaline more effective than noradrenaline in dealingwith hypersensitivity?
During the hypersensitivity reaction, the most important problem to deal with is BREATHING. Adrenaline is more selective for beta receptors than noradrenaline so is better at causing beta-2 mediated bronchodilation, thus opening up the airways. Adrenaline also stimulates the heart via beta-1 to support blood pressure. Adrenaline also acts on the alpha-1 receptors to cause vasoconstriction and an increase in TPR and blood pressure. Adrenaline can also slow down the release of histamine from mast cells via beta-2.
173
State two pulmonary obstructive conditions in which adrenaline is used therapeutically and explain why.
Asthma Acute bronchospasm associated with chronic bronchitis or emphysema It causes beta-2 mediated bronchodilation and it suppressors mediator release. Selective beta-2 agonists are preferable, though adrenaline is useful in a hypotensive crisis.
174
Which receptors are involved in the generation of aqueous humour in the eye?
Alpha-1 involved in vasoconstriction of the vessels in the ciliary body Beta-receptors control the enzyme that makes the aqueous humour
175
Why is adrenaline used as a treatment for glaucoma?
Adrenaline can stimulate the alpha-1 receptors to cause vasoconstriction of the vessels in the ciliary body thus reducing the blood flow within the ciliary body -\> reduced production of aqueous humour
176
State and explain three other clinical uses of adrenaline.
Cardiogenic Shock (the sudden inability of the heart to pump sufficientoxygenated blood)  Beta-1 stimulation has a positive inotropic effect  Cardiogenic shock can happen in MI or cardiac arrest Spinal Anaesthesia  Anaesthetising through the spine can take away the sympathetic output to the peripheral resistance vessels  This leads to relaxation of the peripheral vasculature so the patient can’t maintain their blood pressure  Giving a little adrenaline with the anaesthetic can constrict the blood vessels to maintain blood pressure Local Anaesthesia  Giving adrenaline with the LA can cause local vasoconstriction, which prevents clearance of the anaesthetic from that area  This is due to alpha-1 mediated vasoconstriction
177
State some unwanted actions of adrenaline.
Secretions are reduced and thick CVS – tachycardia, palpitations, arrhythmias, cold extremities, hypertension Overdose of adrenaline can lead to: cerebral haemorrhage, pulmonary embolism
178
Describe the resistance to degradation of phenylephrine.
Phenylephrine is MORE resistant to COMT degradation than adrenaline but it is NOT resistant to MAO degradation
179
State some clinical uses of phenylephrine.
Mydriatic Nasal decongestant It causes vasoconstriction
180
Describe and explain the effects of clonidine.
Clonidine stimulates alpha-2 receptors so has a negative effect on NA synthesis and release. Decrease in NA release -\> less vasoconstriction via alpha-1 action -\> fall in TPR and blood pressure Clonidine also has a central action on the brainstem – acts on baroreceptors and reduces the sympathetic drive coming out of the brain. Reduction in sympathetic activity reduces TPR and reduces the amount of NA released at the nerve terminals thus reducing TPR further. So there are two routes of clonidine action in reducing NA release and TPR. Alpha-2 mediated reduction in NA release in the kidneys will also reduce renin release and hence reduce angiotensin II.
181
State some clinical uses of clonidine.
It is used to treat hypertension and migraine.
182
Describe the susceptibility to breakdown of isoprenaline compared to adrenaline.
Isoprenaline is less susceptible to uptake 1 and MAO breakdown
183
State three clinical uses of isoprenaline.
Cardiogenic Shock Myocardial Infarction Acute Heart Failure
184
What is a big problem with isoprenaline with regards to its action on beta 2 receptors?
Isoprenaline brings about positive effects via Beta-1 stimulation However, stimulation of Beta-2 leads to vasodilation of blood vessels in the muscles -\> pooling of blood within the muscles -\> reduced venous return Via the baroreceptors, you get a reflex tachycardia So the beta-1 effects are good for patients with heart failure but the beta-2 effects are not
185
State a clinical use of dobutamine.
Cardiogenic shock It lacks isoprenaline’s reflex tachycardia effect Administration via IV infusion (half-life = 2 mins)
186
Describe the relative resistance of salbutamol to degradation.
Relative resistance to MAO and COMT
187
State and explain two clinical uses of salbutamol.
Asthma ï‚· Beta-2 mediated relaxation of bronchial smooth muscle (bronchodilation) ï‚· Inhibition of release of bronchoconstrictor molecules from mast cells Threatened premature labour ï‚· Beta-2 mediated relaxation of uterine smooth muscle ï‚· This will prevent abortion
188
State some side effects of salbutamol.
Reflex tachycardia Tremor Blood glucose dysregulation
189
State two indirectly acting SNS agonists.
Cocaine Tyramine
190
Describe the mechanism of action of cocaine.
Cocaine inhibits uptake 1 for both noradrenaline and dopamine leading to an accumulation of dopamine or noradrenaline within the synapse
191
Which nucleus within the hypothalamus uses dopamine as its neurotransmitter?
Nuclues accumbens
192
Describe the effects of cocaine on the CNS and CVS.
CNS ï‚· Low dose = euphoria ï‚· High dose = activation of chemotactic trigger zones (causing vomiting), CNS depression, respiratory failure, convulsions, death CVS ï‚· Low dose = tachycardia, vasoconstriction, raised blood pressure ï‚· High dose = ventricular fibrillation and cardiac arrest
193
What is tyramine and what foodstuffs is it found in?
It is a dietary amino acid Found in cheese, soy sauce and red wine
194
Describe the mechanism of action of tyramine.
Tyramine acts as a false transmitter It acts as a weak agonist at the effector organ at which NA will be stimulating receptors It piggy backs on the uptake systems and competes with NA for the uptake 1 site Tyramine starts being taken up into vesicles and it displaces NA from the vesicles Normally MAO breaks down the displaced NA
195
In which subset of patients is tyramine a problem?
Patients taking MAO inhibitors This means that the break down of NA is inhibited so it accumulates in the synapse leading to a hypertensive crisis
