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► Med - Anatomy & Physiology > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

In the sympathetic system, what does coupling through Gs protein activate?

A

Adenylyl cyclase to increase [cAMP]

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2
Q

During sympathetic activity, once the Gs protein has activated adenylyl cyclase to increase [cAMP], what occurs?

A

Increased heart rate (positive chronotropic effect) - mediated by SA node and due to an increased slope of the pacemaker potential.

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3
Q

During the parasympathetic system, what two things does coupling through Gi protein do?

A
  1. Decreases activity of adenylate cyclase and reduces [cAMP]
  2. Opens potassium channels to cause hyperpolarisation of SA node
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4
Q

In the parasympathetic system, what does acetylcholine activating M2 muscarinic cholinoceptors ultimatley lead to?

A

Decreased heart rate (negative chronotropic effect) - mediated by the SA node and due to decreased slope of the pacemaker potential

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5
Q

In relation to the generic SA node cell action potential, what causes the upstroke?

A

Either Na channels or L-type Ca channels responsible

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6
Q

In relation to the generic SA node cell action potential, what causes the downstroke?

A

Na and Ca channels shut and K channels open

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7
Q

What is an inward current, activated by hyperpolarisation?

A

Funny current (If)

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8
Q

What carries the funny current?

A

Sodium

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9
Q

What does the balance of increasing inward and decreasing outward currents cause? (funny current)

A

Diastolic depolarisation

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10
Q

What occurs as a result of blockage of HCN channels?

A

Decreases the slope of the pacemaker potential and reduces heart rate

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11
Q

Name a selective blocker of HCN channels?

A

Ivabradine

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12
Q

What is ivabradine used for?

A

To slow heart rate in angina (a condition in which coronary artery disease reduces the blood supply to cardiac muscle). Slower rate reduces O2 consumption.

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13
Q

Name 3 things the funny current is blocked by?

A
  1. Acetylcholine
  2. Specific bradycardiac agents (SBAs)
  3. Alinidine, UL-FS49, Ivabradine
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14
Q

What are channels responsible for the funny current activated by?

A
  1. Hyperpolarisation

2. Cyclic AMP [called hyperpolarisation-activated cyclic nucleotide gated (HCN) channels]

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15
Q

Name two substances which can modulate the funny current?

A

ACh

Isoprenaline

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16
Q

Name the beta-adrenergic agonist which signals via cAMP to increase heart rate?

A

Isoprenaline

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17
Q

Name the muscarinic agonist that decreases cAMP and decreases heart rate?

A

ACh

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18
Q

What do an increase in thyroid hormones, increased in VIP & NPY, decrease in adenosine and increase in nitric oxide all cause?

A

Modulation of funny current

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19
Q

What do hormones that increase cAMP do?

A

Increase heart rate

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20
Q

What do drugs that block funny current reduce?

A

Heart rate and oxygen demand

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21
Q

Sympathetic stimulation: what results from an increase in phase 2 of the cardiac action potential, enhanced Ca2+ entry and sensitisation of contractile proteins to Ca2+?

A

Increased contractility

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22
Q

Sympathetic stimulation: What causes an increase in conduction velocity in AV node?

A

Enhanced activity of voltage-dependent Ca2+ channels

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23
Q

What does increased automaticity mean (caused by sympathetic stimulation)?

A

Tendency for non-nodal regions to acquire spontaneous activity

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24
Q

Sympathetic stimulated decreases duration of systole - why does that occur?

A

Increased uptake of Ca2+ into the sarcoplasmic reticulum

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25
Q

What happens to the cardiac efficiency after sympathetic stimulation?

A

Decreases (with respsect to O2 consumption)

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26
Q

In parasympathetic stimulation, what does derease in phase 2 of cardiac action potential and decreased Ca2+ entry cause?

A

Decreased contractility

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27
Q

In parasympathetic stimulation, what does decreased conduction in AV node result from?

A

Decreased activity of volatge-dependent Ca2+ channels and hyperpolarisation via opening of K+ channels.

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28
Q

What might cause dysrhythmias to occur in the atria?

A

Parasympathetic stimulation

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29
Q

What is the Frank-Starling relationship?

A

An intrinisc property of cardiac muscle (i.e. not under hormonal control)

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30
Q

What are the 3 reasons that stretch increases venous return? (Frank-Starling relationship)?

A
  1. Increases skeletal muscle activity
  2. Adrenergic effects on blood vessels - increased venous tone
  3. Respiratory pump - increased depth and frequency respiration
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31
Q

The rise in intracellular calcium activates contraction after a delay. What is this rise in intracellular calcium called?

A

The calcium transient

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32
Q

How is cardiac transient measured?

A

Using the fluoresecence indicator Fluo-3

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33
Q

What occurs after the action potential has sweeped across the cell and dived down into the t-tubules?

A

Voltage-gatyed L-type calcum channels located in the t-tubule membrane are opened by the depolarisation and they let in a small amount of calcium

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34
Q

What occurs after voltage-gated L-type Ca channels located in the t-tubule membrane are opened by the depolarisation and let in small amounts of calcium?

A

Sarcoplasmic reticulum calcium release channels release a larger amount of calcum through the process of calcium-induced calcium release

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35
Q

What does sarcoplasmic reticulum calcium release channels releasing large amounts of calcium through the process of calcium-induced calcium relelease cause?

A

Calcium in the cytoplasm to be elvated from 100nM to 1uM in about 30 msec

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36
Q

Once calcium in the cytoplasm has elevated from 100nM to 1uM in 30msec, what is activated?

A

The calcium activates the myofilaments and contraction occurs

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37
Q

Once calcium has activated the myofilaments and contraction has occured, what happens next to cause relaxation?

A

Calcium is removed from the cytoplasm by the SR Ca ATPase (SERCA) and the sarcolemmal Na/Ca exchanger, which brings about relaxation.

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38
Q

What causes bigger calcium transients and bigger twitches?

A

Isoprenaline

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39
Q

What are the 4 sites of action of PKA in hormonal control of cardiac output?

A
  1. RyR
  2. LTCC
  3. PLB
  4. Tnl
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40
Q

Give three things about regulation of voltage-gated calcium channels?

A
  1. Phosphorylated by protein kinase A
  2. Increases trigger calcium
  3. Increases calcium induced calcium release
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41
Q

What are the two functions of Ryanodine receptors?

A
  1. Calcium channel

2. Calcium induced calcium release from SR

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42
Q

Give two things about regulation of ryanodine receptors?

A
  1. Protein kinase A activates

2. Increases size of calcium transient

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43
Q

What is the function of SERCA 2a?

A

Removal of calcium at the end of the beat

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44
Q

Say 4 things about the regulation of SERCA 2a?

A
  1. Phospholamban (PLB, indirect)
  2. PKA phosphorylation of PLB
  3. Increases calcium uptake by SERCA
  4. Accelerates relaxation
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45
Q

Give the function of troponin?

A

Troponin regulates the actin/myosin interaction using Ca

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46
Q

Give three things about the regulation of troponin?

A
  1. Troponin is phosphorylated by protein kinase A
  2. Phosphorylation reduces the affinity for calcium
  3. Minor reduction in contraction; accelerates relaxation
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47
Q

What does troponin I ohosphorylation have an effect on?

A

Calcium binding member of the troponin complex, troponin C

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48
Q

What effect does troponin I phosphorylation have on tropnin c?

A

Reduce calcium affinity - reduce calcium sensitivity

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49
Q

What are the two most important contributors to positive inotrpy?

A

Phospholamban and the ryanodine receptor

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50
Q

What does phospholamban phosphorylation activate and what does it promote?

A

Activates SERCA and promotes relaxation by turning the beat off quicker, as well as increasing the amount of calcium in teh SR.

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51
Q

What causes an increase in the amount of calcium released from the SR each beat?

A

Ryanodine receptor

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52
Q

What does L-type calcium channel phosphorylation increase the amount of?

A

Trigger calcium needed to initiate a contraction

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53
Q

What leads to a recued affinity of troponin C for calcium?

A

Troponin I phosphorylation

This accelerates relaxation

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54
Q

What does phospholemman phosphorylation (both PKA and PKC) lead to?

A

Sodium pump activation which is important in maintaining the sodium gradient

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55
Q

What phosphorylation leads to a higher rate of sodium calcium exchange?

A

NCX phosphorylatyion (PKC)

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56
Q

What does a high rate of sodium calcium exchange mean?

A

Increases the trigger calcium at the start of an action potential, and accelerates calcium removal at the end of a beat

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57
Q

What is the ejection fraction?

A

The fraction of the blood in the left ventricle that is pumped out in each beat.

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58
Q

Give three factors that increase end diastolic volume, which increases force of contraction through the Frank-Starling mechanism?

A
  1. Decreased venous compliance through adrenergic stimulation
  2. Increased skeletal muscle activity
  3. Respiratory pump
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59
Q

How do hormones increasing cAMP and activating PKA increase the force of contraction?

A

By increasing Ca influx and release

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60
Q

How do hormones increasing cAMP and activating PKA shorten the contractile cycle?

A

By increasing Ca reuptake

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61
Q

Name three beta-adrenoceptor agonists?

A

Dobutamine
Adrenaline
Noradrenaline

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62
Q

Give three pharmacodynamic effects of beta-adrenoceptor agonists on the heart

A
  1. Increased force, rate and cardiac output (HR x SV) and oxygen consumption
  2. Decreased cardiac efficiency (oxygen consumption increased more than cardiac work)
  3. Can cause disturbances in cardiac rhythm (arrhythmias)
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63
Q

What drug can be used for cardiac arrest (sudden loss of pumping function), emergency treatment of asthma and anaphylactic shock (life threatening respiratory distress and often vascular collapse)?

A

Adrenaline

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64
Q

Name a selective B1-adrenoceptor, used for acute, but potentially reversible, heart failure (e.g. following cardiac surgery, or cardiogenic shock)

A

Dobutamine

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65
Q

What do the physiological effects of beta-adrenoceptor blockade depend upon?

A

The degree to which the sympathetic nervous sytem is activated.

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66
Q

What is the name of a non-selective beta-blocker, antagonist of B1 and B2?

A

Propanolol

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67
Q

What are the pharmacodynamic effects of beta-adrenoceptor antagonists at rest?

A

Little effect on rate, force, CO or MABP

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68
Q

What are the pharmacodynamic effects of beta-adrenoceptor antagonists during exercise or stress?

A

Rate, force and CO are significantly depressed - reduction in maximal exercise tolerance

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69
Q

What pharmacodynamic effects happen to the coronary vessel diameter by beta-adrenoceptor antagonists?

A

Marginally reduced (B-adrenoceptors mediate vasodilatation in small coronary vessels, but myocardial oxygen requirement falls even further, thus better oxygenation of the myocardium.

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70
Q

Name two selective b1-blockers?

A
  1. Metoprolol

2. Atenolol

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71
Q

What are the 4 treatment uses of beta-adrenoceptor antagonists?

A
  1. Treatment of disturbances of cardiac rhythm (dysrythmias)
  2. Treatment of hypertension (HT)
  3. Treatment of angina
  4. Treatment of heart failure
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72
Q

What can lead to tachycardia, or spontaneous activation of ‘latent cardiac pacemakers’ outside nodal tissue?

A

Excessive sympathetic activity associated with stress or disease (heart failure or MI)

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73
Q

What decreases excessive sympathetic drive and help restore normal sinus rhythm (i.e. rhythm driven by the SA node)?

A

B-blockers

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74
Q

What is cardiac output defined as?

A

Heart rate x stroke volume

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75
Q

What drugs can cause bronchospasm (block airway smooth muscle b2-adrenoceptors) and are dangerous in asthmatics?

A

Bronchospasm

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76
Q

What side effect do b-blockers have on cardiac failure?

A

Aggravate it

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77
Q

What can b-blockers do to heart rate as a side effect?

A

Bradycardia (heart block - in patients with coronary disease; b-adrenoceptors facilitate nodal conduction)

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78
Q

What side effect can b-blockers have on glucose levels?

A

Hypoglycaemia (in patients with poorly controlled diabetes - the release of glucose from the liver is controlled by b2-adrenoceptors). Also tachycardia in response to hypoglycaemia is a warning mechanism.

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79
Q

What is another side effect of b-blockers in relation to energy?

A

Fatigue - CO and skeletal muscle perfusion in excersise are regulated by b-adrenoceptors

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80
Q

What can happen to peripheral temperature as a side effect of beta-blockers?

A

Cold extremities - loss of beta-2-adrenoceptor mediated vasodilatation in cutaneous vessels

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81
Q

Name a non-selective muscarnic receptor antagonist?

A

Atropine

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82
Q

Give three pharmacodynamic effects of atropine on the heart?

A
  1. Modest increase in heart rate (tachycardia) in normal subjects - more pronounced effect in highly trained athletes (who have increased vagal tone)
  2. No effect upon arterial BP (resistance vessels lack a parasympathetic innervation)
  3. No effect upon the response to exercise
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83
Q

Give three clinical uses of atropine?

A
  1. To reverse bradycardia following MI (in which vagal tone is elevated)
  2. As an adjunct to anaesthesia
  3. In anticholinesterase poisoning (to reduce excessive parasympathetic activity)
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84
Q

Name a cardiac glycoside that increases contractility of the heart

A

Digoxin

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85
Q

What does digoxin block to increase the contractility?

A

The sarcolemma Na/K ATPase

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86
Q

What actively maintains ion gradients; contributes to Vm?

A

Na/K ATPase

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87
Q

What does the Na/Ca exchanger do?

A

Couples the chemical and electrical gradient driving Na influx to Ca efflux

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88
Q

What does digoxin do to the Na/K ATPase?

A

Blocks it

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89
Q

Which drug increases Na intracellular concentration and decreases Vm?

A

Digoxin

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90
Q

What drug decreases Na/Ca exchange and increases Ca intracellular concentration?

A

Digoxin

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91
Q

What does digoxin do to the storage of Ca in SR?

A

Increases it

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92
Q

What does digoxin do to CICR and contractility?

A

Increases it

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93
Q

How does digoxin bind?

A

Binds to the alpha-subunit of Na/K ATPase in competition with K

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94
Q

What can effects of digoxin be dangerously enhanced by?

A

Low plasma (K+), hypokalaemia

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95
Q

What indirect effect does digoxin have on vagal activity?

A

Increases it

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96
Q

What does digoxin do to the SA node discharge, AV node conduction and refractory period?

A

Slows SA node discharge

Slows AV node conduction; increases refractory period

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97
Q

What does digoxin have a direct effect on?

A

Shortens teh action potentials and refractory period in atrial and ventricular myocytes; toxic concentration cause membrane depolarisation and oscillatory afterpotentials

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98
Q

What is an increase in AV node refractory period beneficial to?

A

Heart failure coupled with AF (effects upon the AV node helps to prevent spreading of the dysrhythmia to the ventricles)

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99
Q

Give two side effects of digoxin?

A
  1. Excessive depression of AV node conduction (heart block)

2. Propensity to cause dysrhythmias

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100
Q

Name a calcium-sensitiser? (inotropic drugs)

A

Levosimendan

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101
Q

How does levosimendan work?

A

Binds to troponin C in cardiac muscle sensitising it to the action of calcium

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102
Q

What does cross bridge formation between actin and myosin result in?

A

Contraction

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103
Q

What drug additionally opens Katp channels in vascular smooth muscle causing vasodilation and is a relatively new agent, used in treatment of acute decompensated heart failure?

A

Levosimendan

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104
Q

Name 4 types of drugs that are vasodilators?

A
  1. Calcium antagonists
  2. Alpha blockers
  3. ACE inhibitors (ACE)
  4. Angiotensin receptor blockers (ARB)
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105
Q

Name three broad classes of anti hypertensive drugs?

A

Thiazide diuretics
Beta blockers
Vasodilators

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106
Q

Name 4 types of antianginal drugs

A
  1. Beta blockers
  2. Calcium antagonisits
  3. Nitrates
  4. Nicorandil
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107
Q

Give three broad classes of anti-thrombotic drugs

A
  1. Antiplatelet drugs
  2. Anticoagulants
  3. Fibrinolytics
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108
Q

Name two antiplatelet drugs?

A

Aspirin

Clopidogrel

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109
Q

Name an anticoaglant?

A

Warfarin

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110
Q

Name two fibrinolytics

A

Streptokinase

tPA

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111
Q

Give two examples of anti cholesterol drugs?

A

Statins

Fibrates

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112
Q

What drugs block Na reabsorption in kidneys?

A

Diuretics

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113
Q

What diuretics are mild and used in hypertension?

A

Thiazide diuretics

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114
Q

Name a thiazide diuretic?

A

Bendrofluazide

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115
Q

What diuretics are stronger and used in heart failure?

A

Loop diuretics

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116
Q

Name a loop diuretic?

A

Furosemide

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117
Q

Give 4 side effects of diuretics

A
  1. Hypokalaemia (tired, arrythmias)
  2. Hyperglycaemia (diabetes)
  3. Increased uric acid (gout)
  4. Impotence
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118
Q

What drugs block beta-1 and beta-2 adrenoceptors?

A

Beta-blockers

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119
Q

What beta-blockers only block beta-1 receptors and are used in angina, hypertension and heart failure?

A

Cardioselective beta-blockers

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120
Q

Name a cardioselective beta-blocker?

A

Atenolol

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121
Q

What beta-blockers block beta-1 and beta-2 receptors and are used in thyrotoxicosis?

A

Non selective beta-blockers

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122
Q

Name a non selective beta-blocker?

A

Propanolol

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123
Q

Give 3 side effects of beta-blockers?

A
  1. Tired
  2. Heart failure
  3. Cold peripheries
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124
Q

What should you never use beta-blockers in?

A

Patients with asthma

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125
Q

Decribe the beta-blocker effect on heart failure*?

A

Beta-blockers are good in medium/long term heart failure but can worsen heart failure in short term.

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126
Q

What are the two types of calcium antagonists?

A
  1. Dihydropyridines

2. Rate limiting calcium antagonists

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127
Q

Which calcium antagonists are used in hypertension and angina, but also have ankle oedema as a side effect?

A

Dihydropyridines

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128
Q

Give an example of a dihydropyridine?

A

Amlodipine

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129
Q

What calcium antagonists are used in hypertension and angina, plus supraventricular arrhythmias (AF, SVT), but should be alerted when given with beta-blockers?

A

Rate limiting calcium antagonists

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130
Q

Give two examples of rate limiting calcium antagonists?

A

Verapamil

Diltiazem

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131
Q

What drugs block alpha adrenoceptors to cause vasodilation?

A

Alpha blockers

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132
Q

What drugs are used in hypertension and prostatic hypertrophy?

A

Alpha blockers

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133
Q

Name an alpha blocker?

A

Doxazosin

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134
Q

Give one side effect of alpha blockers?

A

Postural hypertension

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135
Q

What drugs block angiotensin I from becoming angiotensin II?

A

ACE inhibitors

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136
Q

Give an example of an ACE inhibitor?

A

Lisinopril

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137
Q

What drugs are used in hypertension and heart failure, good for kidneys in diabetic nephropathy and are bad for kidneys in renal artery stenosis?

A

ACE inhibitors

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138
Q

What are 3 side effects of ACE inhibitors?

A
  1. Dry cough
  2. Renal dysfunction
  3. Angioneurotic oedema
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139
Q

What drugs should you never use in pregnancy induced hypertension?

A

ACE inhibitors

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140
Q

Which drugs block angiotensin II receptors?

A

Angiotensin receptor blockers (ARBs)

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141
Q

Give an example of an angiotensin II receptor blocker (ARB)?

A

Losartan

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142
Q

What are ARBs used in?

A

Hypertension and heart failure

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143
Q

What are ARBs good for and bad for in relation to kidneys?

A
  1. Good for kidneys in diabetic nephropathy

2. Bad for kidneys in renal a stenosis

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144
Q

Give two side effects of ARBs?

A
  1. Renal dysfunction

2. No cough

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145
Q

Can ARBS be used in pregnancy induced hypertension?

A

No

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146
Q

What drugs are venodilators?

A

Nitrates

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147
Q

Give an example of a venodilator (nitrate)?

A

Isosorbide monoritrate

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148
Q

What are nitrates used in?

A

Angina and acute heart failure

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149
Q

Give two side effects of nitrates

A
  1. Headache

2. Hypotension/collapse

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150
Q

What drugs prevent new thrombosis?

A

Antiplatelet agents

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151
Q

What drugs are used in angina, acute MI, CVA/TIA and patients with high risk of MI & CVA?

A

Antiplatelet drugs

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152
Q

Give three side effects of antiplatelet agents?

A
  1. Haemorrhage anywhere
  2. Peptic ulcer = haemorrhage
  3. Aspirin sensitivity = asthma
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153
Q

What do anticoagulants prevent?

A

New thrombosis

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154
Q

Give two anticoagulants?

A
  1. Heparin IV

2. Warfarin oral

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155
Q

What does warfarin oral block?

A

Clotting factors (2, 7, 9, 10)

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156
Q

What drugs are used in DVT, PE, NSTEMI and AF?

A

Anticoagulants - WARFARIN

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157
Q

Give a side effect of anticoagulants?

A

Haemorrhage anywhere

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158
Q

How do you control the dose of anticoagulants?

A

Usisng INR

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159
Q

What reverses warfarin?

A

Vitamin K

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160
Q

Name two other anticoagulants, other than heparin and warfarin?

A
  1. Rivaroxaban

2. Dabigatran

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161
Q

What is Rivaroxaban?

A

A factor X a inhibitor

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162
Q

What is Dabigatran?

A

Thrombin (factor IIa) inhibitor

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163
Q

What does Xa convert?

A

Prothrombin II to thrombin IIa

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164
Q

What drugs dissolve formed clots?

A

Fibrinolytic drugs

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165
Q

Name one fibrinolytic drug?

A

Streptokinase

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166
Q

Name a tissue plasminogen activator (tPA)?

A

Streptokinase

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167
Q

What are fibrinolytic drugs used in?

A

STEMI, PE, CVA

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168
Q

Give a side effect of fibrinolytic drugs?

A

Haemorrhage serious risk

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169
Q

What drug type should you avoid in: recent haemorrhage (some CVA), trauma, bleeding tendencies, severe diabetic retinopathy and peptic ulcers?

A

Fibrinolytic drugs (streptokinase)

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170
Q

Name two broad classes of anticholsterol drugs?

A
  1. Statins

2. Fibrates

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171
Q

Give an example of a statin?

A

Simvastatin

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172
Q

How does simvastatin work?

A

Blocks HMG CoA reductase.

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173
Q

Name a drug used in hypercholesterolaemia, diabetes, angina/MI, CVA/TIA, high risk patients for MI and CVA?

A

Simvastatin (statins)

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174
Q

Give two side effects of statins?

A

Myopathy

Rhabdomyolysis renal failure

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175
Q

Give an example of a fibrate?

A

Benzafibrate

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176
Q

What is benzafibrate used in?

A
  1. Hypertriglyceridaemia

2. Low HDL cholesterol

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177
Q

What anti arrythmic drug would be used in acute phase of supraventricualr arrythmias (e.g. SVT)?

A

Adenosine

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178
Q

What 3 anti arrythmic drugs are used in ventricular/supraventricular arrhythmias?

A

Amiodarone
Betablockers
Flecainide

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179
Q

Name an anti-arrythmic long-acting drug?

A

Amiodarone

180
Q

Give three side effects of anti arrhythmic drugs?

A
  1. Phototoxicity
  2. Pulmonary fibrosis
  3. Thyroid abnormalities (hypo or hyper)
181
Q

What drug blocks atrial-ventricular conduction and produces a degree of A-V conduction delay?

A

Digoxin

182
Q

Name a good drug for AF?

A

Digoxin

183
Q

What occurs when digoxin is given excessivly?

A

Heart rate falls too much giving bradycardia and heart block

184
Q

What drug increases ventricular irritability which produces ventricular arrythmias and has a narrow therapeutic index?

A

Digoxin

185
Q

Give 4 outcomes of digoxin toxicity?

A
  1. Nausea, vomiting
  2. Yellow vision
  3. Bradycardia, heart block
  4. Ventricular arrhythmias
186
Q

Contraction of smooth muscle cell: Once the intracellular calcium is increasing, what converts it to Ca2+-CaM?

A

calmodulin

187
Q

In smooth muscle contraction: what does Ca2+-CaM convert?

A

MLCK to MLCK (active)

188
Q

In smooth muscle contraction: what does MLCK (active) convert?

A

Myosin-LC to Myosin-LC P

189
Q

During smooth muscle relaxation: what converts myosin-LC-phosphatase to Myosin-LC-phosphatase (active)?

A

cGMP

190
Q

In smooth muscle relaxation: what does myosin-LC-phosphatase (active) convert?

A

Myosin-LC P to Myosin-LC

191
Q

What do vasodilating substances like bradykinin, ADP and 5-HT cause in endothelial cells?

A

Increased intracellular calcium

192
Q

In endothelial cells, once intracellular calcium has increased and joined to CaM, what does Ca2+-CaM release?

A

eNOS

193
Q

What does eNOS in endothelial cells convert?

A

(L-arginine + oxygen) to (NO + citrulline)

194
Q

Once NO is in a smooth muscle cell, what does it do?

A

Goes to Guanylate cyclase and converts GTP to cGMP

195
Q

In smooth muscle cells, once GTP has converted to cGMP, what does cGMP release?

A

Protein kinase G causing relaxation

196
Q

As well as protein kinase G, what else causes relaxation in a smooth muscle cell?

A

Hyperpolarisation

197
Q

When organic nitrates such as GTN move into smooth muscle cells, what do they react with and what do they produce?

A

React with enzymes/tissue thiol (SH) groups to release NO

198
Q

What substances relax all types of smooth muscle via their metabolism to NO?

A

Organic nitrates

199
Q

What effect do organic nitrates cause that as a result causes: [decreased CVP (preload) reduces SV, but CO maintained by increased HR, no change in arterial pressure]?

A

Venorelaxation

200
Q

What dose amount is required for organic nitrates to venorelax?

A

Small doses

201
Q

What dose amounts are required for organic nitrates to cause arteriolar dilatation?

A

High doses

202
Q

What effect of organic nitrates causes [decreased arterial pressure reducing afterload]. Large muscular arteries are more sensitive, reduces pulse wave reflection from arterial branches?

A

Arteriolar dilatation

203
Q

What do organic nitrates do to coronary blood flow?

A

Increase (in angina there is no overall increase, but blood is redirected towards the ischaemic zone)

204
Q

In angina, benifits are derived from decreased myocardial oxygen requirement, via what 3 features?

A
  1. Decreased preload
  2. Decreased afterload
  3. Improved perfusion of the iscaemic zone
205
Q

Give two organic nitrate examples that are used in angina?

A
  1. Glyceryltrinitrate (GTN)

2. Isosorbide mononitrate

206
Q

How long does GTN take to work and why?

A 
30 minutes (short acting)
Undergoes extensive first pass metabolism
207
Q

How is GTN administered?

A

Sublingually for rapid effect before exertion (stable angina) or IV (in conjunction with aspirin) in unstable angina

208
Q

How long does isosorbide moninitrate take to work and why?

A 
longer acting (half-life = 4 hours)
Resistant to first pass metabolism
209
Q

How is isosorbide mononitrate administered?

A

Orally for prohylaxis and a more sutained effect

210
Q

Name two antagonists of the ETa receptor?

A
  1. Bosentan

2. Ambrisentan

211
Q

What are bosentan and ambrisentan (antagonists of the ETa receptor) used in?

A

The treatment of pulmonary hypertension

212
Q

What do adrenaline, angiotensin II and ADH cause to happen in the endothelial cell, in relation to vascular smooth muscle tone?

A
  1. Alter gene expression

2. Endothelin precursor to make endothelin-1

213
Q

What does endothelin-1 act on, on the membrane of smooth muscle cells?

A

ETa receptors

214
Q

What two drugs act on the RAAS?

A

ACE inhibitors and ARBs

215
Q

What plays a major role in sodium excretion and vascular tone?

A

RAAS

216
Q

What receptor does angiotenin II react on?

A

AT1 receptor (GPCR)

217
Q

In relation to RAAS, what causes tubular Na+ reabsorption and salt retention?

A

Aldosterone secretion from adrenal cortex

218
Q

Angiotensin II reacting on AT1 receptor causes contraction of vascular smooth muscle due to what two things?

A
  1. Activation of smooth muscle AT1 receptors

2. Increased release of noradrenaline from sympathetic nerves

219
Q

What is aliskiren?

A

A renin inhibitor

220
Q

Where do ARBs work on?

A

AT1 receptors

221
Q

What two functions does ACE (membrane bound enzyme on surface of endothelial cells) have?

A
  1. Converts angiotensin I to angiotensin II (vasoconstrictor)
  2. Inactivates bradykinin (vasodilator)
222
Q

What drugs block the agonist action of angiotensin II at AT1 receptors in a competetive manner?

A

AT1 receptor antagonists (sartans)

223
Q

What drugs cause venous dilatation (decreased preload) and arteriolar dilatation (decreased afterload and TPR) decreasing arterial blood pressure and cardiac load?

A

ACE inhibitors

224
Q

Do ACE inhibitors effect cardiac contractility?

A

No

225
Q

What do ACE inhibitors do to the release of aldosterone?

A

Reduce the release of aldosterone (decrease in circulating levels of aldosterone promotes loss of Na and H2O)

226
Q

What drugs reduce direct growth action of angiotensin II upon the heart and vasculature?

A

ACE inhibitors

227
Q

What do ACE inhibitors do that ARbs dont?

A

Inhibit the metabolism of bradykinin

228
Q

What should ARBs and ACE inhibitors not be used in?

A

Pregnancy (foetal toxicity)

Bilateral renal artery stenosis

229
Q

In cardiac failure, what do ARBs and ACE inhibitors do, 3 things?

A
  1. Decrease vascular resistance improving perfusion
  2. Increase excretion of Na+ and H20
  3. Cause regression of left ventricular hypertrophy
230
Q

What are adrenoceptors?

A

G-protein coupled receptors (GPCR) that are activatged by the sympathetic transmitter NA and the hormone adrenaline.

231
Q

What adrenoceptor causes vasoconstriction?

A

Alpha-1

232
Q

What adrenoceptor causes increased heart rate, force, and AV node conduction velocity?

A

Beta-1 adrenoceptor

233
Q

What adrenoceptors cause bronchodilatation and relaxation?

A

Beta-2 adrenoceptors

234
Q

What are beta-adrenoceptor antagonists used in?

A

Treatment of angina pectoris (not variant angina)

235
Q

What three effects do B-blockers (particularly beta-1- selective agents) have of value to angina?

A
  1. Decrease myocardial oxygen requirements (decreased HR and SV = decreased workload and decreased oxygen)
  2. Counter elevated sympathetic activity associated with ischaemic pain
  3. Increase the amount of time spent in diastole (decreased HR), improving perfusion of the left ventricle
236
Q

When does the window for coronary blood flow occur in the cardiac cycle?

A

During diastole

237
Q

What three ways do beta-blockers help restore normal blood pressure?

A
  1. Reducing cardiac output
  2. Reducing renin release from kidney
  3. A CNS action that reduces sympathetic activity
238
Q

What do calcium antagonists prevent?

A

The opening of L-type channels in excitable tissues in response to depolarisation and hence limit (the increase of intracellular calcium)

239
Q

Where do all clinically useful calcium antagonists interact?

A

With L-type calcium channels found in the heart and smooth muscle

240
Q

What two things do L-type channels mediate?

A
  1. Upstroke of the action potential in the SA and AV nodes

2. Phase 2 of the ventricular action potential

241
Q

During phase 2 of the ventricular AP, what can calcioum antagonists reduce?

A

Force of contraction

242
Q

During upstroke of AP in the SA and AV node, what can calcium antagonists reduce?

A

Rate and conduction through the AV node

243
Q

In vascular smooth muscle, what provides a pathway for calcium entry into cells?

A

L-type channels

244
Q

In smooth muscle cells, what happens after NA is released from poastganglionic sympathetic neurone and reacts with alpha-1-adrenoceptor?

A

Alpha-1-adrenoceptor releases calcium from intracellular stores (SR)

245
Q

What three clinical things can calcium antagonists be used for?

A

Hypertension
Angina
Dysrythmias

246
Q

What do calcium antagonists cause, that is particularly useful in patients with angina and hypertension?

A

Coronary vasodilatation

247
Q

Give three side effects of calcium antagonists?

A
  1. Hypotension
  2. Dizziness and flushing
  3. Swollen ankles
248
Q

What are calcium channel blockers often used in combination with for prophylactic treatment of angina?

A

GTN

249
Q

What two calcium antagonists produce negative inotropic effects but latter offset by activation of the baroreceptor reflex in response to vasodilatation and increased sympathetic activity?

A

Diltiazem and verapamil

250
Q

How do calcium channel blockers help in dysrhythmias?

A

Ventricular rate in rapid atrial fibrillation reduced by suppression of conduction through the AV node.

251
Q

What calcium antagonist is usually used for dysrhythmias, but should be avoided in heart failure, especially in combination with a beta-blocker?

A

Derapamil

252
Q

Name two potassium channel openers?

A

Minoxidil and Nicorandil

253
Q

What drugs open ATP-modulated K+ channels (Katp) in vascular smooth muscle?

A

Potassium channel openers

254
Q

What drugs act by antagonising intracellular ATP (which closes the Katp channel)?

A

Potassium channel openers

255
Q

What do potassium channel openers cause, which switches off L=type Ca2+ channels?

A

Hyperpolarisation

256
Q

What drug is used as a last resort in severe hypertension but causes reflex tachycardia (prevented by a b-blocker) and salt and water retention (alleviated by a diuretic)?

A

Minoxidil

257
Q

Which drug (which also has NO donor activity) is used in angina refractory to other treatments?

A

Nicorandil

258
Q

How do alpha-1-adrenoceptors receptor antagonists cause vasodilatation?

A

By blocking vascular alpha-1-adrenoceptors. Reducd sympathetic transmission results in decreased MABP.

259
Q

Name two alphablockers? (both are competetive antagonists)

A

Prazosin

Doxazosin

260
Q

What is benign prostatic hyperplasia?

A

An abnormally enlarged prostate that compresses the urethra

261
Q

What do alpha-adrenoceptor antagonists also provide symptomatic relief in?

A

Benign prostatic hyperplasia and are particularly indicated for hypertensive patients with this condition

262
Q

What drugs act on the kidney to increase the excretion of Na, Cl and H20 and exert additional, indirect, relaxant effects upon the vasculature?

A

Diuretics

263
Q

What are the two classes of diuretics?

A

Thiazides and loop agents

264
Q

Give two features of thiazide diuretics?

A
  1. Inhibit NaCl reabsorption in the distal tubule by blocking the Na+/Cl- co-transporter
  2. Cause up to 5% of filtered Na+ to be excreted along with H2O producing a moderate diuresis
265
Q

Give two features of loop diuretics?

A
  1. Inhibit NaCl reabsorption in the thick ascending limb of the loop of Henle by blocking the Na+/K+/2Cl- co-transporter
  2. Cause up to 15-25% of filtered Na+ to be excreted with accompanying H2O producing a strong diuresis
266
Q

What do thiazide diuretics and loop agents both produce an undesirable loss of and how is it corrected?

A

K+

Corrected by co-administration of a ‘potassium sparring diuretic’ or K+ supplements

267
Q

Name a thiazide widely used in mild heart failure and hypertension, as well as additionally in severe resistant oedema (with a loop agent)

A

Bendroflumethiazide

268
Q

Name a loop diuretic used to reduce salt and water overload associated with acute pulmonary oedema (IV) and chronic heart failure?

A

Furosemide

269
Q

Are lipids soluble in water?n

A

No

270
Q

Give examples of two non-polar lipids?

A

Cholesterol esters and triglycerides

271
Q

How are non-lipids transported in the blood?

A

Within lipoproteins [e.g. HDL and LDL]

272
Q

What two factors is CVS disease (atherosclerosis) strongly associated with?

A
  1. Elevated LDL

2. Decreased HDL

273
Q

What are microscopic spherical particles of 7 to 1000 nM diameter?

A

Lipoproteins

274
Q

What two things does a lipoprotein consist of?

A
  1. Hydrophobic core containing esterified cholesterol triglycerides
  2. Hydrophilic coat comprising a monolayer of amphipathic cholesterol, phospholipids and one or more apoprotein
275
Q

What are the 4 major lipoproteins?

A
  1. HDL particles
  2. LDL particles
  3. Very-low desnsity lipoprotein (VLDL) particles
  4. Chylomicrons
276
Q

What particles cosntain apoB-100 and have diameter of 3-80 nM?

A

Very-low density lipoprotein

277
Q

What lipoproteins contain apoB-48 and have a diameter of 100-1000 nM?

A

Chylomicrons

278
Q

What is the role of ApoB-containing lipoproteins?

A

Deliver triglycerides to muscle for ATP biogenesis and adipocytes for storage

279
Q

Where are chylomicrons formed and what do they transport?

A

Formed in intestinal cells and transport dietary triglycerides - the exogenous pathway

280
Q

Where are VLDL particles formed and what do they transport?

A

VLDL particles are formed in liver cells and transport triglycerides synthesised in that organ - the endogenous pathway

281
Q

What are the 3 steps that summarise the life-cycle of ApoB-containing liposomes?

A
  1. Assembly [with apoB100 in the liver and apoB48 in the intestine]
  2. Intravascular metabolism (involving hydrolysis of the triglyceride core)
  3. Receptor mediated clearance
282
Q

During the assembly of apoB-containing lipoprotein chylomicron: what does cholesterol react with to enter the enterocyte?

A

Niemann-Pick C1-like 1 protein (NPC1L1)

283
Q

During the assembly of apoB-containing lipoprotein chylomicron: what enters the enterocyte, that came from digestion of dietary fat (25%) and bile (75%)?

A

Cholesterol

284
Q

During the assembly of apoB-containing lipoprotein chylomicron: What two substanes from digestion of dietary fat, enter the enterocyte to make triglycerides?

A
  1. Monoglyceride

2. Free fatty acid (long chain)

285
Q

During the assembly of apoB-containing lipoprotein chylomicron: Once cholesterol has entered the enterocyte, what happens?

A

It is esterified to become a cholesterol ester

286
Q

During the assembly of apoB-containing lipoprotein chylomicron: What does the ribosome produce?

A

apoB48

287
Q

During the assembly of apoB-containing lipoprotein chylomicron: What does apoB48 bind to?

A

Triglyceride

288
Q

During the assembly of apoB-containing lipoprotein chylomicron: what mediates lipidation of apoB48 triglyceride?

A

MTP - Microsomal Triglyceride Transfer Protein

289
Q

During the assembly of apoB-containing lipoprotein chylomicron: what substance mediates the conversion of lipidated, apoB48 triglyceride to a chylomicron with cholesterylester?

A

MTP

290
Q

During the assembly of apoB-containing lipoprotein chylomicron: what is added to the chylomicron before it exits the enterocyte by exocytosis?

A

Second apoprotein apoA1

291
Q

During the assembly of apoB-containing lipoprotein chylomicron: what happens when the chylomicron exits the enterocyte?

A

It enters lymphatics and is carried in lymph to systemic circulation (subclavian vein) via the thoracic duct.

292
Q

Where are VLDL particles containing triglycerides assembled?

A

In liver hepatocytes

293
Q

What substances make VLDL particles containing triglycerides?

A

Free fatty acids from adipose tissue and de novo synthesis

294
Q

During the assembly of apoB-containing lipoproteins VLDL particles, what does MTP lipidate?

A

apoB100 forming nascent VLDL that coalesces with triglyceride droplets

295
Q

To target triglyceride delivery to adipose and muscle tissue, what must happen to chylomicrons and VLDL?

A

Must be activated

296
Q

What activates chylomicrons and VLDL particles?

A

Transfer of apoCII from HDL particles

297
Q

Name a lipolytic enzyme associated with the endothelium of capillaries in adipose and muscle tissue?

A

LPL

298
Q

What does apoCII facilitate?

A

Binding of chylomicrons and VLDL particles to LPL

299
Q

What does LPL hydrolyse, of which the end substances enter tissues?

A

Core triglycerides to free fatty acids and glycerol

300
Q

What are chylomicron and VLDL remnants?

A

Particles depleted of triglycerides (but still containing cholesteryl esters) are termed chylomicron and VLDL remnants.

301
Q

Clearance of apoB-containing lipoproteins: what causes chylomicrons and VLDL particles to become relatively enriched in cholesterol due to triglyceride metabolism?

A

LPL

302
Q

Clearance of apoB-containing lipoproteins: what happens once LPL has caused chylomicrons and VLDL particles to become relatively enriched in cholesterol due to triglyceride metabolism?

A

Chylomicrons and VLDL dissociate from LPL

303
Q

Clearance of apoB-containing lipoproteins: what happens after chylomicrons and VLDL have dissociated from LPL?

A

ApoCII is transferred to HDL particles in exchange for apoE which is a high affinity ligant for receptor mediated clearance. Particles are now remnants.

304
Q

Clearance of apoB-containing lipoproteins: what happens after the particles have become remnants?

A

Remnants return to the liver and are further metabolised by hepatic lipase

305
Q

Clearance of apoB-containing lipoproteins: what happens once the remnants have returned to the liver and are further metabolised by hepatic lipase?

A

All apoB48-containing remnants and 50% of apo100 containing remnants are cleared by receptor mediated endocytosis into hepatocytes

306
Q

Clearance of apoB-containing lipoproteins: what occurs as the last stage, after all apoB48 containing remnants and 50% of apo100 containing remnants are cleared by receptor-mediated endocytosis into hepatoctes?

A

Remaining apoB100-containing remnants loose further triglycerides through hepatic lipase, become smaller and enriched in cholesteryl ester and via intermediate density lipoproteins (IDL) become LDL particles lacking apoE and retaining solely apoB100.

307
Q

Clearance of apoB-containing lipoproteins: what is clearance of LDL particles crucially dependent on?

A

LDL receptor expressed by the liver and other tissues

308
Q

How does cellular uptake of LDL particles occur?

A

Via receptor-mediated endocytosis

309
Q

Clearance of apoB-containing lipoproteins: within the cell at the lysosome, what is released by hydrolysis?

A

Cholesterol from cholesteryl ester

310
Q

What is the rate limiting enzyme in de novo cholesterol synthesis?

A

HMG-CoA reductase

311
Q

What 3 things does released cholesterol cause?

A
  1. Inhibition of HMG-CoA reductase
  2. Down regulation of LDL receptor expression
  3. Storage of cholesterol as cholesterol ester
312
Q

What is a focal disease of large and medium sized arteries?

A

Atherosclerosis

313
Q

Give three risk factors for atherosclerosis?

A
  1. Diabetes
  2. Smoking
  3. High BP
314
Q

What is atherosclerosis initiated by?

A

Dysfunction and injury of the lining (endothelium) of blood vessels

315
Q

During the disease progression of atherosclerosis: what is uptaken into the intima of the artery from the blood, and what then occurs to it?

A

LDL

Subsequently oxidised to atherogenic oxidised LDL (OXLDL)

316
Q

During the disease progression of atherosclerosis: once OXLDL has formed, what migrates across the endothelium?

A

Monocytes (white blood cells) across the endothelium into the intima where they become macrophages

317
Q

During the disease progression of atherosclerosis: once macropahges are involved, what then occurs?

A

Uptake of OXLDL by macrophages converts them to cholesterol-laden foam cells that form a fatty streak.

318
Q

During the disease progression of atherosclerosis: how do macrophages uptake OXLDL?

A

Using scavenger receptors

319
Q

During the disease progression of atherosclerosis: What cells form fatty streaks?

A

Cholesterol-laden foam cells

320
Q

During the disease progression of atherosclerosis: Once cholesterol-laden foam cells have caused a fatty streak, what does release of inflamamtory substances from various cell tpyes cause?

A

Division and proliferation of smooth muscle cells into the intima and the deposition of collagen.

321
Q

During the disease progression of atherosclerosis: once collagen has been deposited into the intima, what occurs?

A

The formation of an atheromatous plaque consitsting of a lipid core (product of dead foam cells) and a fibrous cap (smooth muslce cells and connective tissue).

322
Q

What does HDL have a key role in?

A

Removing excess cholesterol from cells by transporting it in plasma to the liver.

323
Q

What is the only organ that has the capacity to eliminate cholesterol from the body (as cholesterol secreted into bile, or used to synthesise bile salts)?

A

Liver

324
Q

What substance is mainly formed in the liver, initially as apoA1 in association with a small amount of surface phospholipid and unesterified cholesterol (pre-beta-HDL)?

A

HDL

325
Q

What does disc-like pre-beta-HDL mature in the plasma to become?

A

Spherical alpha-HDL

326
Q

What occurs alongside disc-like pre-beta-HDL maturing in the plasma to spherical alpha-HDL?

A

Surface cholesterol is enzymatically converted to hydrophobic cholesterol ester that migrates to the core of teh particle.

327
Q

What is reverse cholesterol transport?

A

Mature HDL accepts excess cholesterol from the plasma membrane of cells (e.g. macrophages) and delivers cholesterol to the liver.

328
Q

What receptor does HDL reaching the liver interact with, and what does it allow?

A

Scavenger receptor-B1, SR-B1, that allows transfer of cholesterol and cholesteryl esters into hepatocytes

329
Q

In the plasma, what mediates transfer of cholesteryl esters from HDL to VLDL and LDL, indirectly returing cholesterol to the liver?

A

Cholesterol Ester Transfer Protein (CETP)

330
Q

What does primary dyslipidaemia occur through?

A

A combination of diet and genetic factors

331
Q

What is secondary dyslipidaemia a consequence of?

A

Other diseases such as type II diabetes, hypothyroidism, alcoholism and liver disease

332
Q

What are a subset of type IIa hyperlipoproteinaemia associated gene defects in the LDL receptor (familial hypercholesterolaemia) associated with?

A

A great risk of ischaemic heart disease

333
Q

What are the drugs of choice to reduce LDL?

A

Statins

334
Q

What drugs reduce total and LDL cholesterol up to 60%, decrease triglycerides (up to 40%) and modestly increase HDL?

A

Statins

335
Q

Give two examples of statins?

A

Simvastatin and artovastatin

336
Q

What do statins act as a competitive inhibitor of?

A

(HMG-CoA) reductase or 3-hydroxy-3-methylglutaryl coenzyme A

337
Q

What converts HMG-CoA to mevalonate?

A

HMG-CoA reductase

338
Q

What do statins do to hepatocyte cholesterol synthesis?

A

Drecrease it causing a compensatory increase in LDL receptor expression and enhanced clearanc of LDL

339
Q

Are statins effective in familial hypercholesterolaemia?

A

No - LDL receptors are lacking

340
Q

What are these 4 features other benifits of - decreased inflammation, reversal of endothelial dysfunction, decreased thrombosis, stabilisation of atherosclerotic plaques?

A

Statins

341
Q

How are statins administered?

A

Orally at night

342
Q

Give two side effects of statins?

A
  1. Myositis

2. Rhabdomyolosis - increased if statin combined with fibrate

343
Q

Give two examples of Fibrates?

A
  1. Benzofibrate

2. Gemfibrozil

344
Q

What drugs cause a pronounced decrease in triglycerides (50%) and modest decrease (up to 15%) and increase (up to 20%) in LDL and HDL, respectively?

A

Fibrates

345
Q

What are the first line drugs in patients with very high triglyceride levels?

A

Fibrates

346
Q

What do fibrates act as an agonist of to enhance the transctiption of several genes including that encoding LPL?

A

Nuclear receptor (PPARalpha)

347
Q

What patients are you best to avoid fibrate use in?

A

Alcoholics predisposed to hypertriglyceridaemias

348
Q

Give three adverse effects of fibrates other than myositis

A
  1. GI symptoms
  2. Pruritus
  3. Rash
349
Q

Name a type of drug that inhibits cholesterol absorption?

A

Bile acid binding resins

350
Q

Name 3 bile acid binding resins

A
  1. Colestyramine
  2. Colestipol
  3. Colsevelam
351
Q

What drugs cause the excretion of bile salts resulting in more cholesterol to be converted to bile salts by interupting enterohepatic recycling?

A

Bile acid binding resins

352
Q

How are bile acid binding resins administered?

A

Ingested orally, not absorbed from GI tract, prevent the reabsorption of bile salts

353
Q

What substances cause decreased absorption of triglycerides and increased LDL receptor expression?

A

Binding resins

354
Q

Give one adverse effect of bile acid binding resins?

A

GI tract irritation

355
Q

Name a drug used to inhibit Niemann-Pick C1 like-1 (NPC1L1) transport protein in enterocytes of the duodenum, reducing the absorption of cholesterol

A

Ezetimibe

356
Q

What does ezetimibe do to LDL and HDL?

A

Decreases LDL

Little change to HDL

357
Q

What is ezetimibe used in combination with, if the latter is not achieving a sufficient response?

A

Statinsd

358
Q

How is ezetimibe administered?

A

Orally, metabolised to an active metabolite that undergoes enterohepatic recycling that contributes to a long half-life of approximately 22 hours

359
Q

Give three adverse effects of ezetimibe?

A

Diarrhoea
Abdominal pain
Headache

360
Q

What is exetimibe contraindicated in?

A

Breast feeding females

361
Q

What is the term for arrest of blood loss from a damaged blood vessel?

A

Haemostasis

362
Q

What three things does haemostasis involve?

A
  1. Local vasoconstriction
  2. Adhesion and activation of platelets at site of injury
  3. Formation of fibrin (blood coagulation)
363
Q

What is the term for pathological haemostasis - a haematological plug in the absence of bleeding?

A

Thrombosis

364
Q

What are the predisposing factors (Virchow’s triad) for thrombosis?

A
  1. Injury to vessel wall (e.g. ruptured atheromatous plaque)
  2. Abnormal blood flow
  3. Increased coaguability of the blood
365
Q

What is a white thrombus?

A

Arterial thrombus

366
Q

What is a red thrombus?

A

Venous thrombus

367
Q

What is the name for - mainly platelets in a fibrin mesh?

A

White thrombus

368
Q

What forms an embolus if it detaches from its site of origin (left heart, carotid artery) often lodges in an artery in the brain (stroke) or other organ?

A

White, arterial thrombus

369
Q

What thrombus has a white head, jelly-like tail and is fibrin rich?

A

Red thrombus - venous thrombus

370
Q

What thrombus type usually causes pulmonary embolism when it detaches as an embolus that lodges in the lung?

A

Red thrombus, venous thrombus

371
Q

What are the three steps involved in platelet reactions to form a clot, after endothelial damage?

A
  1. Adhesion, activation and aggregation of platelets
  2. Secretion of preformed mediators (ADP) and synthesis of mediators (e.g. TXA2)
  3. Further aggregation of platelets
372
Q

What is the final substance in blood coagulation which leads to a fibrin clot?

A

Fibrin

373
Q

What converts to fibrin, and what mediates this conversion?

A

Fibrinogen to fibrin

Mediated by thrombin IIa

374
Q

What do thrombin IIa and fibrinogen cause?

A

Further aggregation of platelets

375
Q

What forms thrombin IIa, and what mediates this reaction?

A

Prothrombin II to thrombin IIa

Mediated by Xa

376
Q

What is converted to Xa?

A

X

377
Q

In the vivo pathway for endothelial damage, what two substances are present that convert X to Xa?

A

Tissue factor and factor VIIa

378
Q

In the contact pathway of endothelial damage, which two factors are present, which convert X to Xa?

A

XIIa and XIa

379
Q

What are glycoprotein precursors of the active factors thrombin IIa, VIIa, IXa and Xa?

A

Clotting factors prothrombin II, VII, IX and X

380
Q

What do thrombin IIa, VIIa, IXa and Xa act as?

A

Serine proteases

381
Q

Give an example of a post-translational modification that precursors require for subsequent function of the active factors?

A

Gamma-carboxylation of glutamate residues

382
Q

What does the carboxylase enzyme that mediates gamma-carboxylation require?

A

Vitamin K in its reduced form as an esential cofactor

383
Q

What does warfarin block?

A

Vitamin K reductase

384
Q

What converts vitamin K oxidised form (epoxide) to vitamin K reduced form (hydroquinone)?

A

Vitamin K (quinone)

385
Q

What converts - (oxygen + CO2 + glutamic acid residues [in II (descarboxyprothrombin), VII, IX, X]) to (gamma-carboxyglutamic acid residues [in prothrombin II, VII, IX, X])?

A

Conversion of vitamin K reduced form to vitamin K oxidised form

386
Q

What drugs are used widely in the prevention and treatment of venous thrombosis and embolism?

A

Anticoagulants

387
Q

What drugs can be used as treatment for DVT, post-operative thrombosis, patients with artifical heart valves and atrial fibrillation patients?

A

Anticoagulants

388
Q

What do anticoagulants all carry the risk of?

A

Haemorrhage

389
Q

What is a coumarin derivative structurally related to vitamin K, competes with vitamin K for binding to hepatic vitamin K reductase preventing the conversion of the epoxide to the active hydroquinone?

A

Warfarin

390
Q

What drug renders factors II, VII, IX and X inactive?

A

Warfarin

391
Q

What does warfarin block coagulation in?

A

In vivo and not vitro

392
Q

How is warfirin administered and how long is its onset of action?

A

Orally

2-3 days

393
Q

Why does warfarin have a slow onset of action?

A

Wait, whilst inactive factors replace active gamma-carboxylated factors that are slowly cleared from the plasma. Heparin may be added for rapid anticoagulant effect.

394
Q

What can it be difficult to strike the balance with, when using warfarin?

A

Desired anticoagulant effect and haemorrhage - low therapeutic index

395
Q

What must warfarin be monitored with?

A

INR

396
Q

Give two factors that potentiate warfarin action (risk of haemorrhage increased)?

A
  1. Liver disease - decreased clotting factors

2. High metabolic rate - increased clearance of clotting factors

397
Q

What 3 factors cause the risk of thrombosis to increase when using warfarin?

A
  1. Pregnancy (increased clotting factor synthesis)
  2. Hypothyroidism (decreased degradation of clotting factors)
  3. Vitamin K consumption
398
Q

What two things can be used to treat overdose of warfarin?

A
  1. Vitamin K

2. Conentrate of plasma clotting factors

399
Q

What is an important inhibitor of coagulation which neutralises all serine protease factors in the coagulation cascade by binding to their active site in a 1 to 1 ratio?

A

Antithrombin III

400
Q

What binds to antithrombin III, increasings its affinity for serine protease clotting factors (particularly Xa and thrombin IIa) to greatly increase their rate of inactivation?

A

Heparin

401
Q

What is Xa inhibited by?

A

Antithrombin III and heparin

402
Q

What inhibits thrombin IIa?

A

Antithrombin III and heparin

403
Q

What must heparin bind to both of to inhibit thrombin IIa?

A

Both antithrombin III and thrombin IIa

404
Q

What msut heparin bind to to inhibit Xa?

A

Only antithrombin III

405
Q

What drug is a naturally occuring sulphated glycosaminoglycan of variable molecular size (unfractionated) and is also extracted from beef lung, or hog intestine?

A

Heparin

406
Q

Name two low molecular weight heparins?

A
  1. Enoxaparin

2. Dalteparin

407
Q

What do LMWHs inhibit and not inhibit?

A

Inhibit factor Xa

Do not inhibit thrombin IIa

408
Q

In what two ways can heparin be administered?

A

IV or subcutaneously

409
Q

What is required to determine optimum dosage for heparin?

A

In vitro clotting test

410
Q

What does elimination of heparin show?

A

Zero order kinetics whereas that of HMWHs is first order

411
Q

How is LMWH eliminated from the body?

A

Via renal excretion, hence heparin is preferred in renal failure

412
Q

Give 4 adverse effects of heparin and LMWHs?

A
  1. Haemorrhage - discontinue drug and adminsiter protamine sulfate
  2. Osteoporosis (long term treatment)
  3. Hypoaldosteronism
  4. Hypersensitivity reactions
413
Q

Give a drug which is a direct inhibitor of thrombin?

A

Dabigatran

414
Q

Give a drug which is a direct inhibitor of factor Xa?

A

Rivoroxaban

415
Q

What drugs are used to prevent venous thrombosis in patients undergoing hip and knee replacements?

A

Dabigatran and rivaroxaban

416
Q

What does endothelial cell damage, or rupture of the cap of an atheromatous plaque lead to?

A

Platelet activation and aggregation, arterial thrombosis and potentially MI (heart attack)

417
Q

How do platelets adhere to subendothelial molecules, revealed by vascular damage?

A

Via surface glycoproteins (GPIb receptors) with von Willebrand factor acting as a ‘bridge’.

418
Q

What happens to platelets once they have adhered to GPIb receptors with von Willebrand factors?

A

Change shape and subsequently aggregate.

419
Q

What two platelet derived substances drive aggregation?

A
  1. Secretion of adenosine diphosphate (ADP), 5-HT and coagulation factors from storage granules
  2. Thromboxane A2 synthesis via the enzyme cyclo-oxygenase (COX)
420
Q

What do ADP, 5-HT and TXA2 act on cell surface receptors of platelets to cause?

A

Expression of GPIIb/IIIa receptors that cross link platelets via fibrinogen.

421
Q

What does exposure of acidic phospholipid on platelet surface promoting thrombin IIa formation stimulate?

A

Further aggregation, stabilised by formation of fibrin from fibrinogen.

422
Q

What does tirofiban block?

A

Fibrinogen binding with GPIIb/IIa receptors

423
Q

What does clopidogrel block?

A

Irreversibility of ADP

424
Q

What mediates arachidonic acid generation to production of cyclic endoperoxides?

A

Cyclo-oxygenase-1 (COX-1)

425
Q

What does production of cyclic endoperoxidases lead to?

A

The synthesis of TXA2

426
Q

What does aspirin block irreversibly?

A

Cyclo-oxygenase-1 (COX-1)

427
Q

What are used mainly in the treatment of arterial thrombosis?

A

Anti-platelet drugs

428
Q

What does aspirin’s blockage of COX in endothelial cells inhibit?

A

The production of antithrombotic prostaglandin I2

429
Q

What can endothelial cells synthesis, that new enucleate platelets cannot?

A

COX enzyme

430
Q

What drug is used orally, mainly for thromboprophylaxis in patients at high cardiovascular risk

A

Aspirin

431
Q

Give two adverse effects of aspirin?

A

GI bleeding

Ulceration

432
Q

Which drug links to P2Y12 receptor by a disulphide bond producing irreversible inhibition?

A

Clopidogrel

433
Q

Which drug, when administered orally and combined with aspirin has a synergistic action?

A

Clopidogrel

434
Q

Which drug is given in short term treatment to prevent MI in high risk patients with unstable angina (along with aspirin and heparin)?

A

Tirofiban

435
Q

What exists endogenously and opposes the coagulation cascade?

A

A fibrinolytic cascade

436
Q

Which class of drugs are used principally to reopen occluded arteries in acute MI or stroke, less frequently in life-threatening venous thrombosis or PE?

A

Fibrinolytics

437
Q

How should fibrinolytics be administered?

A

IV within as short a period as possible to the event

438
Q

What is superior to fibrinolytic drugs when treating MI or stroke - but has to be available pronptly?

A

Percutaneous coronary intervention (PCI)

439
Q

Which three fibrinolytic drugs activate plasminogen?

A
  1. Streptokinase
  2. Alteplase
  3. Duteplase
440
Q

What is not an enzyme, but a protein extracted from cultures of streptococci?

A

Streptokinase

441
Q

What is the action of streptokinase blocked by after 4 days?

A

The production of antibodies

442
Q

Which drug primarily reduces mortality in acute MI?

A

Streptokinase

443
Q

What two drugs are recombinant tissue plasminogen activator (rt-PA)?

A

Alteplase and duteplase

444
Q

How are alteplase and duteplase administered?

A

IV - short half life

445
Q

What may the major adverse effect of fibrinolytics (haemorrhage) be controlled by?

A

Tranexamic acid which inhibits plasminogen activation.

► Med - Anatomy & Physiology (130 decks)

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