Pharmacology 1 Flashcards
(92 cards)
1
Q
What is phase 0, 3 and 4 of the action potential in nodal tissue of the heart? (3)
A
- Phase 0 - Depolarisation, calcium influx via L-type Ca+ channels (ICAL)
- Phase 3 - repolarisation, inactivation of L-type Ca+ channels and activation of K+ channels causing K+ efflux (delayed rectifier K+ current)
- Phase 4 - pacemaker potential, decrease in K+ efflux, funny current and transient T-type Ca+ channel influx
2
Q
What membrane potential value does upstroke head towards? Downstroke?
A
Positive
Negative
3
Q
Why is downstroke not maintained in pacemaker cells?
A
Pacemaker potential - depolarisation towards threshold
4
Q
What is determined by pacemaker potential slope? (2)
A
HR and AP frequency
5
Q
Why is the AP not very tall in nodal tissue?
A
Background currents act against Ca+ channels (outward movement of positive charge)
6
Q
How are funny current channels activated?
A
Negative membrane potentials (hyperpolarisation)
7
Q
Why is action potential generated far more quickly in atrial and ventricular myocytes than in nodal tissue?
A
- It is the opening of Na+ channels that causes depolarisation in cardiac myocytes
- Na+ channels open much more quickly than Ca++ channels
8
Q
What is another name for phase 4 - resting membrane potential?
A
Diastolic potential
9
Q
What is phase 2 (plateau) a balance between?
A
- Inward Ca+ current that slowly inactivates
* Outward K+ current that slowly activates
10
Q
Can another AP be fired during plateau?
A
No, as NA+ channels are inactivated
11
Q
What is the purpose of plateau?
A
Provides calcium which drives cardiac contraction
12
Q
Why is long duration of plateau beneficial?
A
Stops heart beating too rapidly
13
Q
What does phase 3 involve in cardiac myocyte action potentials?
A
Repolarisation via activation of 2 K+ channels:
- Inward rectifier K+ current
- Delayed rectifier potassium current
14
Q
What do noradrenaline (post-ganglionic transmitter) and adrenaline (adrenomedullary hormone) activate?
A
B1 adrenoceptors in (i) nodal cells and (ii) myocardial cells
(sympathetic)
15
Q
What does activation of B1 adrenoceptor by adrenaline/noradrenaline result in?
A
Coupling through Gs protein activates adenylyl cyclase to increase [cAMP]
16
Q
What is the role of adenylyl cyclase?
A
Conversion of ATP to cAMP
17
Q
What does increased [cAMP] result in? (7)
A
- Positive chronotropic effect
- Positive inotropic effect
- Decrease in AV nodal delay (positive dromotropic effect)
- Increase in automaticity
- Decrease in duration of systole (positive lusitropic effect)
- Increase in activity of Na/K ATPase pump
- Increase in mass of cardiac muscle (cardiac hypertrophy)
18
Q
How does noradrenaline/adrenaline increase pacemaker potential slope?
A
Via enhanced funny current and Ca+ current
19
Q
How does sympathetic system increase heart rate (positive chronotropic effect)? (2)
A
- Increase in pacemaker potential slope
* Reduction in threshold for AP generation
20
Q
How does noradrenaline/adrenaline reduce threshold for AP generation?
A
Enhanced Ca+ current
21
Q
How does sympathetic system increase contractility (positive inotropic effect)? (2)
A
- Increase in phase 2 of AP in atrial and ventricular myocytes (enhanced Ca+ influx)
- Sensitisation of contractile proteins to Ca+
22
Q
How does sympathetic system decrease AV nodal delay (positive dromotropic effect)?
A
Enhancement of funny current and calcium influx
23
Q
What is automaticity?
A
Tendency for non-nodal regions to exhibit spontaneous activity
24
Q
How does sympathetic system decrease duration of systole (positive lusitropic action)?
A
Due to increased uptake of Ca++ into SR
25
What is the importance of sympathetic system increasing the activity of Na/K?ATPase pump?
Important for repolarisation
26
Why is positive lusitropic action advantageous in sympathetic stimulation?
To allow for complete relaxation (refilling) of ventricle before next contraction occurs
27
What does acetylcholine (post-ganglionic transmitter) activate?
M2 muscarinic cholinoceptors in nodal cells (parasympathetic)
28
What does activation of M2 muscarinic receptor by acetylcholine result in?
Coupling through Gi protein:
(i) decreases activity of adenylyl cyclase and reduces [cAMP]
(ii) opens potassium channels (GIRK) to cause hyperpolarization of SA node
29
What does reduced [cAMP] and opening of GIRK channels result in? (3)
* Negative chronotropic effect
* Negative inotropic effect (atria only)
* Negative dromotropic effect (increase in AV nodal delay)
30
How does parasympathetic system decrease heart rate (negative chronotropic effect)? (3)
* Decreased slope of pacemaker potential
* Hyperpolarisation caused by opening of GIRK channels
* Increase in threshold for AP generation
31
How does parasympathetic system decrease pacemaker potential slope? (2)
Reduced funny current and calcium influx
32
How does parasympathetic system increase threshold for AP generation?
Reduced calcium influx
33
How does parasympathetic system cause a negative inotropic effect in the atria?
Decrease in phase 2 of cardiac AP (decreased Ca++ entry)
34
Why does negative inotropic effect (decrease in force of contraction) affect atria only?
Ventricles are only very sparsely innervated by parasympathetic NS - contraction largely unaffected
35
How does parasympathetic system cause a negative dromotropic effect? (2)
* Decreased activity of voltage-gated Ca++ channels
| * Hyperpolarisation via operino of K+ channels
36
What can cause arrhythmias to occur in the atria?
Parasympathetic stimulation
37
What do vagal manoeuvres do? What are they used for?
(i) Increase parasympathetic output
| (ii) Used in atrial tachycardia, atrial flutter and atrial fibrillation to suppress impulse conduction through AV node
38
What are examples of vagal manoeuvres? (2)
* Valsalva manoevre - activates aortic baroreceptors
* Massage of bifurcation of carotid artery - stimulates baroreceptors in carotid sinus (not recommended as can cause stroke)
39
What is pacemaker potential modulated by?
Funny current channels (depolarising)
40
What are funny current channels activated by? (2)
* Hyperpolarisation
| * Cyclic AMP
41
What are funny current channels called?
Hyperpolarisation-activated Cyclic Nucleotide-gated (HCN) channels
42
How does hyperpolarisation lead to phase 4 (depolarisation) phase?
Activates HCN channels in SA node causing depolarisation
43
What does blockage of HCN channels result in? (2)
* Decreases pacemaker potential slope
| * reduces HR
44
What is an example of a drug used to block HCN channels? What is it used for?
* Ivabradine
| * Used to slow heart rate in angina to reduce O2 consumption and lower need for cardiac blood supply
45
Is Ca++ influx into cytoplasm from L-type channels enough to trigger cardiac muscle contraction?
No, calcium must be amplified
46
How is intra-cellular calcium amplified? How does this facilitate cardiac muscle contraction?
* Ca++ influx into cytoplasm activates ryanodine receptor causing release of Ca++ from SR
* Ca++ binds to troponin C, allowing cross bridge formation between actin and myosin
* Contraction via sliding filaments
47
How is relaxation of cardiac muscle caused? (6)
* Repolarisation (phase 3)
* Inactivation of L-type Ca++ channels
* Ca++ efflux via Na/Ca exchanger 1 (NCX1)
* Active sequestration of Ca++ into SR via Ca++ ATPase
* Ca++ dissociates from troponin C
* Cross bridges break resulting in relaxation
48
What is NCX1?
Antiporter that moves Na+ into cell and Ca+ out
49
What is Ca+ ATPase present in SR called?
SERCA
50
How does B1 adrenoceptor activation modulate cardiac contractility? (6)
* B1 adrenoceptor coupled to Gs protein which activates adenylyl cyclase
* Adenylyl cyclase converts ATP into cAMP
* cAMP activates protein kinase A which phosphorylates L-type Ca+ channel
* Greater calcium influx, increased calcium-induced calcium release meaning greater force of contraction
* PKA also phosphorylates contractile proteins making them more sensitive to calcium and enhancing contractility
* Also phosphorylates phospholamban which increases pumping of Ca+ and thus rate of relaxation
51
What is milrinone?
Phosphodiesterase inhibitor that is seldom used, except IV in acute heart failure
52
What are examples of B-adrenoceptor agonists? (3)
* Dobutamine
* Adrenaline
* Noradrenaline
53
What are dobutamine, adrenaline and noradrenaline classed as?
Catecholamines
54
What are the pharmacodynamic effects of dobutamine, adrenaline and noradrenaline? (2)
* Increase in force of contraction, rate and cardiac output
| * Decrease in cardiac efficiency (increased O2 consumption)
55
What can increase in O2 consumption result in?
Can cause disturbances in cardiac rhythm e.g. arrhythmias
56
What is adrenaline? How is it administered? What is it's half life?
* Mixed agonist acting on both a and B receptors
* IM, SC or IV
* plasma T 1/2 ~2min due to uptake/metabolism
57
What is adrenaline used to treat?
* Cardiac arrest (IV) as part of the advanced life support (ALS) treatment algorithm
* Anaphylactic shock (IM)
58
What are the effects of adrenaline?
* positive inotropic and chronotropic actions (β1)
* redistribution of blood flow to the heart - constricts blood vessels in the skin, mucosa and abdomen (α1)
* dilation of coronary arteries (β2)
59
What is Dobutamine? How is it administered? What is its half life? What is special about Dobutamine?
* Selective B-adrenoceptor agonist
* IV
* plasma T 1/2 ~2 min due to uptake/metabolism
* Causes less tachycardia than other B1 agonists
60
What is Dobutamine used to treat?
Acute but potentially reversible heart failure e.g. following cardiac surgery, cariogenic shock, septic shock
61
What do the physiological effects of B-adrenoceptor blockage depend on?
The degree to which sympathetic nervous system is activated
62
What are examples of non-selective B-adrenoceptor antagonists? (2)
* Propranolol
| * Alprenolol (partial agonist)
63
What are examples of selective B1-antagonists?
* Atenolol
* Bisoprolol
* Metoprolol
64
What are pharmacodynamic effects of non-selective B-adrenoceptor antagonists? (3)
* At rest little effect on rate, force, CO, or MAP (agents with partial agonist activity increase rate at rest, but reduce it during exercise)
* During exercise or stress rate, force and CO are depressed – reduction in maximal exercise tolerance
* Coronary vessel diameter reduced, but myocardial O2 requirement falls, thus better oxygenation of the myocardium
65
What are the pharmacodynamic effects of non-selective B-adrenoceptor partial antagonists?
B blockers with partial agonist will increase rate at rest but decrease rate during exercise
66
What are clinical uses of B-adrenoceptor antagonists? (4)
* Treatment of arrhythmias
* Angina
* Compensated heart failure
* Hypertension
67
What are examples of cardiac arrhythmias? (3)
* Excessive sympathetic activity associated with stress, emotion, heart failure or MI can lead to tachycardia or activation of pacemakers outside of nodal tissue
* Atrial fibrillation
* Supraventricular tachycardia
68
How are beta-blocker used to treat the different kinds of arrhythmia? (3)
* Tachycardia or activation of non-nodal pacemakers - B-blockers decrease excessive sympathetic drive and restore normal sinus rhythm
* Atrial fibrillation and supra ventricular tachycardia - b-blockers day conduction through AV node and restore sinus rhythm
69
Why are beta-blockers used to treat compensated heart failure? Seems paradoxical?
LOW dose beta-blockers (e.g. Carvedilol) improve morbidity and mortality by reducing excessive sympathetic drive
70
What are adverse effects of B-blockers? (6)
* Bronchospasm
* Aggravation of cardiac failure (but low dose b-blockers used in compensated heart failure)
* Bradycardia
* Hypoglycaemia
* Fatigue
* Cold extremities
71
Why are agents like atenolol, bisoprolol and metoprolol preferred?
Less risk associated with B1 selective agents
72
What is an example of a non-selective muscarinic ACh receptor antagonist?
Atropine (competitive antagonist)
73
What are pharmacodynamic effects of non-selective muscarinic ACh receptor antagonists on the heart? (3)
* Increase in HR in normal subjects – more pronounced effect in highly trained athletes (who have increased vagal tone)
* No effect on arterial BP (resistance vessels lack parasympathetic innervation)
* No effect on the response to exercise
74
What are clinical uses for muscarinic ACh receptor antagonists in relation to the heart? (2)
* Treatment of bradycardia (e.g. following MI)
| * Treatment of anti cholinesterase poisoning
75
Why do some practitioners recommend no less than 600 micrograms of atropine?
Low-dose atropine may paradoxically slow heart rate
76
What is Digoxin?
Cardiac glycoside that increases contractility of the heart (inotrope)
77
What is heart failure?
A cardiac output insufficient to provide adequate tissue perfusion
78
What are causes of heart failure?
Any structural, or functional disorder, that impairs the ability of the heart to function as a pump
79
What drugs enhance contractility of the heart?
Inotropic drugs (e.g. digoxin, dobutamine)
80
What is the effect of inotropes on ventricular function curve?
Upward and leftward shift of ventricular function curve so SV increases at any given EDP
81
How does digoxin increase contractility?
By blocking sarcolemma ATPase
82
Explain how digoxin blocks the sarcolemma ATPase (Ca-ATPase) (4)
* Blocks Na/K/ATPase pump meaning intracellular Na+ conc increases
* Less drive for sodium to enter cell meaning sodium calcium pump is lost, resulting in increased intracellular Ca++
* Increased storage of Ca++ in SR meaning increased calcium-induced calcium release
* Increased contractility
83
How does Digoxin block Na/K/ATPase pump?
Binds to a-subunit of Na/K/ATPase in competition with K+
| effects can be dangerously enhanced by low plasma [K+] i.e. hypokalaemia
84
What are the direct effects of digoxin on electrical activity of the heart? (2)
* Shortens action potential and refractory period in atrial and ventricular myocytes (pro-arrhythmic)
* Toxic concentrations cause membrane depolarization and oscillatory afterpotentials (due to Ca2+ overload)
85
What are the indirect effects of digoxin on electrical activity of the heart? (2)
Increases vagal activity which:-
* slows down SA node discharge
* increases AV nodal delay (refractory period)
86
What are clinical uses of digoxin? (3)
* IV in acute heart failure
* Orally in chronic heart failure
* Heart failure with atrial fibrillation
Only used when other drugs do not help in reducing symptoms of heart failure
87
What are adverse effects of digoxin? (6)
* Excessive depression of AV node conduction (heart block)
* Arrhythmias
* Nausea
* Vomiting
* Diarrhoea
* Disturbances of colour vision
Only used when other drugs do not help in reducing symptoms of heart failure
88
What are other classes of inotropic drugs (other than digoxin)? (2)
* Calcium-sensitisers e.g. Levosimendan
| * Inodilators e.g. amrinone and milrinone
89
What is the pharmacodynamics of levosimendan? (2)
* Binds to troponin C in cardiac muscle sensitising it to Ca++ so increases cross bridge formation between actin and myosin and cardiac force
* Opens K+ channels in vascular smooth muscle causing vasodilation (reduces after load and cardiac work)
90
When is levosimendan used clinically?
Treatment of acute decompensated heart failure (IV)
91
What are the effects of amrinone and milrinone (inodilators)? (4)
* Inhibit phosphodiesterase in cardiac and smooth muscle cells so increase cAMP
* Increase myocardial contractility
* Decrease peripheral resistance
* But WORSEN survival :O perhaps due to increased incidence of arrhythmias
92
What are clinical uses of inodilators?
IV in acute heart failure (only used when no other treatment works cause can fucking worsen survival)
