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Exam 1- GI and CVD > Derek warren pharmacology (anti-platelets, coagulation, fibirnolytics etc) > Flashcards

Derek warren pharmacology (anti-platelets, coagulation, fibirnolytics etc) Flashcards

1
Q

What is haemostasis?

A

The cessation of bleeding from a damaged blood vessel (arrest of blood loss)

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2
Q

What happens when LDL cholesterol accumulates in the artery (process of atherosclerosis)?

A
  • The LDL cholesterol accumulates in the endothelial layer of the artery wall
  • LDL becomes oxidised, this triggers endothelial cells to express markers for immune cells
  • immune cells pass into the basement membranes e.g. macrophages and foam cells
  • These cells trigger smooth muscle cells to migrate to the area and proliferate to form a fibrous cap
  • This fibrous cap blocks the entry of cells and debris from the blood
  • Overtime, this thick cap will thin due to death of smooth muscle- the plaque will become unstable and can rupture
  • This exposes the contents of the atherosclerotic plaque to the blood e.g. lipids and debris
  • this leads to a cascade of events- clotting, blockages of arteries = heart attacks or strokes
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3
Q

What happens when we develop a wound?

A

Wound is formed

Leads to vasoconstriction of blood vessels to prevent excess blood loss

Platelet activation and increased adhesion of platelets to the vessel wall

Formation of a haemostat plug (coagulation)

Fibrinolytics will the breakdown the coagulation when ready

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4
Q

What is the main difference in an atherosclerotic coagulation cascade?

A

There is NO bleeding
= Thrombus: the pathological formation of a clot in the vasculature in the absence of bleeding.

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5
Q

What is Thrombosis?

A

the pathological formation of a clot in the vasculature in the absence of bleeding.
Requires prevention drugs

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6
Q

What blood factors activate platelets in the extra-cellular matrix?

A
  • Von willebrand factor
  • Collagen
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7
Q

What factors prevent platelet activation/aggregation?

A

Nitric oxide (NO)
Prostacyclin

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8
Q

How do we inhibit platelets forming blood clots?

A

Target factors that promote activation and aggregation:
Thromboxane A2
ADP
Collagen
Von Willebrand factor

Or stalemate factors that prevent a + a:
Prostacyclin
Nitric oxide

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9
Q

What are examples of anti-platelet drugs?

A

Drugs that decrease aggregation or inhibit thrombus formation:
Aspirin
Clopidogren
Ticragrelor
Glycoprotein iib/iiiab inhibitors e.g. tirotiban, eptifbatide, abciximab

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10
Q

How are platelets adhered to eachtoher?

A

Binded by fibrinogen that binds to glycoprotein iib/iiia receptors on both platelets

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11
Q

How does aspirin work as an anti-platelet?

A
  • Aspirin irreversibly inhibits Cyclooxygenase 1 and 2 (COX-1 & COX-2)

Irreversible inhibition of COX-1 in platelets:
This prevents the production of Thromboxane A2 from Arachidonc acid
- Reduces platelet aggregation as thromboxane normally promotes aggregation

ALSO

Irreversible inhibition of COX-2 in endothelial cells:
- This reduces the formation of prostacyclin
- Prostacyclin usually prevents aggregation (so by inhibiting = increased platelet aggregation)

SO TOGETHER THEY HAVE A NET EFFECS OF ZERO!

BUT this works as:
Endothelial cells can synthesise new cox-2 as they have a nucleus (platelets don’t so can’t synthesise new cox-1) = more cox-2 = more prostacyclin overtime = more preventing aggregation

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12
Q

How do the thienopyridines (clopidogrel, prasugrel) work?

A

They inhibit ADP-induced aggregation by inhibiting the P2Y12 receptor (purinergic receptor) which normally binds ADP and triggers platelet activation- by blocking this receptor- prevents ADP binding = decreased platelet activation and aggregation

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13
Q

How does Ticagrelor work?

A

Is a nucleotide analogue- mimics adenosine
- It blocks the P2Y12 ADP receptors by acting as an allosteric inhibitor (doesn’t directly compete for binding with adp = reversible)

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14
Q

How do glycoprotein iib/iia receptor antagonists work?

A

Prevent the binding of fibrinogen to allow aggregation by occupying the gp iib/iiia receptors that fibrinogen uses to form bridges between adjacent platelets.

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15
Q

What is the coagulation cascade?

A

The formation of a fibrin clot
Process:
leads to conversion of of soluble fibrinogen to insoluble fibrin
2 pathways:
INTRINSIC: Exposure to abnormal surface e.g. glass
All components are present in blood
EXTRINSIC: Switched on in presence of tissue damage- release tissue factor
Some components from outside of blood

Both paths converge at factor 10- cleaved to 10a
= cleavage of prothrombin to thrombin. Thrombin cleaves fibrinogen to small insoluble fibrin fragments
- is activated by factor x111- further strengthens fibrin links
= Fibrinogen –> Fibrin –> Polymer formed- CROSS-LINKED fibrin clot

LOOK AT DIAGRAM

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16
Q

What are the different treatment options depending on whether the patient has a red thrombi or white thrombi (platelet-rich)?

A

White= antiplatelets
Red = anticoagulants

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17
Q

What are some of the anti-coagulants available?

A
  • injectable e.g heparin
  • oral e.g. warfarin
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18
Q

What do heparin activate?

A

Activates antithrombin III
- This inactivates thrombin and factor x a (10a)

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19
Q

What are the types of heparins?

A

Unfractionated
low molecular weight

UFH- inhibits thrombin and Xa
LMWH- Mainly habits factor Xa- more predictable

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20
Q

What are the advantages of using low-molecular weight heparins over unfractioned heparins?

A
  • LMWH bind to endothelial and plasma proteins = increases bioavailability = more available to function
  • Dose is more predictable as it only affects factor Xa
  • Decreased dose frequency
  • Decreased side effects as only targets 1 factor
  • Can be used at home = more convenient
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21
Q

How does warfarin work?

A

Competitively inhibits vitamin K reductase and therefore inhibits the formation of factors II, VII, IX & X (as vitamin K is essential for synthesis of coagulation factors). Also anticoagulation protein C and it cofactor protein S

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22
Q

Does warfarin have effects on clots existing before treatment is initiated?

A

NO- as it acts indirectly- it reduces clotting factors so will only prevent new clots

23
Q

Is warfarin ok to be used in pregnancy or breastfeeding?

A

Warfarin is not used in pregnancy or breastfeeding as it is lipophilic and can cross the placenta and also can enter breastmilk - can be harmful to baby

24
Q

What are fibrinolytic drugs used for?

A

Used to resolve and remove clots by degrading fibrin via plasmin enzymes.

25
Q

What proenzyme is plasmin formed from?

A

plasminogen

26
Q

How do fibrinolytic drugs work?

A

Plasminogen proenzyme needs to be activated e.g. via Tissue plasmin activators (tpa), urokinase or kallikrein
- This causes plasminogen to be cleaved to the active plasmin
- Plasmin binds to fibrin and degrades the fibrin clot into fibrin degradation biproducts

27
Q

What drugs are used to stimulate fibrinolysis?

A
  • Drugs that convert plasminogen to plasmin e.g. streptokinase
  • Recombinant human TPA e.g. Alteplase, Reteplase, Tenecteplase
  • Urokinase
28
Q

What is the important therapeutic point regarding streptokinase?

A

It is antigenic- so we form antibodies to it after 4 days of use. Therefore, once it has been given it CAN’T be re-given for 1 year

29
Q

What kind of conditions is alteplase (and tenectoplase and recteplase) used for, and how is it given?

A

Decreases mortality associated with MI also in strokes, DVT, pulmonary embolisms
- works best when given within 6-12 hours of stroke or blood clot ( but ideally 1 hour)
- is NOT antigenic unlike streptokinase

30
Q

What happens is coronary blood flow is disrupted?

A

The coronary artery carries blood to the heart, if blood flow is disrupted then the cardiomyocytes die.

31
Q

What is the issue with oxygen supply and demand in angina and how can we help this?

A

Normally oxygen supply and demand is balanced but in angina, supply is limited!

REDUCE OXYGEN DEMAND:
= decrease cardiac workload:
- Reduce perfusion demands = rest, decrease stress, decrease smoking, lose weight
- Reduce preload- use vasodilator e.g. nitrates
- Reduce after load- Arterial dilators e.g. CCBS, nitrates

REDUCE CARDIAC RATE/CONTRACTILITY:
- negative inotrope/chronotrope e.g. beta-blockers or CCBs

IMPROVE EFFICIENCY OF HEART:
- increase exercise
- Stop smoking

IMPROVE OXYGEN SUPPLY
- Arterial dilator e.g. CCB, nitrate- work on smooth muscle cells
- Surgery- bypass, angioplasty, stents

32
Q

What are some examples of anti-anginal agents?

A
  • Organic nitrates
  • Calcium channel blockers
  • Beta-blockers
  • Potassium channel activators
33
Q

What are examples of organic nitrates used as anti-anginals?

A
  • Glyceryl trinitrate- used in acute attacks as have quick onset and short duration
  • Isosorbide mononitrate- longer duration of action
34
Q

How do organic nitrates work when used as anti-anginal agents?

A

They act as nitric oxide (NO) donors, the release of no causes smooth muscle relaxation which dilates the blood vessels towards the heart and reducing the stress on the heart by improving blood flow.

35
Q

Why are lower doses of organic nitrates preferable for use in angina?

A

lower doses cause:
Dilation of larger veins=
Decrease in central venous pressure and decrease in cardiac output and oxygen consumption
It has little effects on arterioles or blood pressure

BUT
Higher doses:
Cause arteriolar dilation
Decreased blood pressure
Reduced
Headaches

36
Q

How does nitric oxide work as a vasodilator?

A

NO is related in response to shear stress and causes smooth muscle relaxation:

Nitrates = donors that release NO radicals
Activates granulate cyclase
GTP –> cGMP
Dephosphorylation of myosin light chain
Vasodilation = smooth muscle relaxation
Decreased workload and decreased oxygen consumption

37
Q

How do beta-blockers work for treating angina?

A

They decrease oxygen consumption
slow the heart rate
depress the myocardium
No effects on coronary arteries
increase exercise capacity

38
Q

What are the 3 classes of CCBs with examples?

A

Phenylalkylamines e.g. Verapamil
Dihydropyridines e.g. Nifedipine, Amlodipine
Benzothiazepines e.g. Diltiazem

39
Q

How do CCBs work for treating angina?

A

Inhibit calcium ion entry by depolarisation of tissues:
- verapamil is relatively cardioselective
- nifedipine is relatively smooth muscle selective
- diltiazem is intermediate
Cardiac actions:
Antidysrhythmic effects- due to impaired av conduction = decreased contractility
Negative chronotropic and inotropic effects

vasucular smooth muscle:
Arteriolar dilation = decrease in blood pressure (decreased after load)
Coronary vasodilation

They stop calcium from entering the cells of the heart and arteries. Calcium causes the heart and arteries to squeeze more strongly. By blocking calcium, calcium channel blockers allow blood vessels to relax and ope

40
Q

What are the classes of drugs in the Vaughan-williams classification of anti-arrhythmic drugs?

A

Class 1: Sodium channel blockers (Types A e.g. Disopyramide, B e.g. lidocaine/phenytoin and C e.g. flecainide)
Class 2: Beta-blockers e.g. propranolol, metoprolol
Class 3: Potassium channel blockers e.g. Amiodarone, Sotalol
Class 4: Calcium channel blockers e.g. verapamil, diltiazem

41
Q

What is class 1 of the Vaughan-williams classification of anti-arrhythmic drugs?

A

Na+ channel blockers
Type A - disopyramide
Type B - lidocaine, phenytoin
Type C- flecainide

42
Q

What is class 2 of the Vaughan-williams classification of anti-arrhythmic drugs?

A

Beta-blockers e.g. propranolol, metoprolol

43
Q

What is class 3 of the Vaughan-williams classification of anti-arrhythmic drugs?

A

Class 3: Potassium channel blockers e.g. Amiodarone, Sotalol

44
Q

What is class 4 of the Vaughan-williams classification of anti-arrhythmic drugs?

A

Class 4: Calcium channel blockers e.g. verapamil, diltiazem

45
Q

What stages of the heart beat do each of the Vaughan-william class drugs act on?

A

LOOK AT DIAGRAM!!!
1= Na+ in
2= K+ rectifier
3= K+ out
4= Ca2+ in
(check)

46
Q

How do the class 1, sodium channels blockers work in treating arrhythmias?

A

They decrease depolarisation rate (phase 0) of the heart as they block the entry of Na+ into the into cardiomyocytes- decrease excitability of membrane. (work on cardiomyocyte ap)
Classes are determined based on their effect on effect on action potential:
1a= lengthens action potential (right shift)
1b = shorten action potential (left shift)
1c= no effect on duration of action potential (no shift)

47
Q

How do the class 2, beta blockers work in treating arrhythmias?

A

Have predominant action at the SA node- pacemaker cell action and NOT the cardiomyocyte action potential. They act on beta-1 adrenoreceptors preventing action of catecholamines on the heart.
- They decrease the rate of the slow drift to threshold potential and so increased the time in-between action potential firing = slows heart rate. Also, slow conduction through av node = reduced contractility.
- By blocking effects of catecholamines at Beta-1 adrenoreceptors = reduces cAMP and therefore, intracellular Ca2+

48
Q

How do the class 3, potassium channels blockers work in treating arrhythmias?

A

These drugs work on the cardiomyocyte action potential not SA node pacemaker cells.
K+ ions are needed for repolarisation
So when potassium is blocked, the action potential is widened as the repolarisation of the membrane is slowed.

49
Q

How do the class 4, CCBs work in treating arrhythmias?

A

The CCBs block voltage-sensitive calcium channels during depolarisation particularly in the SA and AV nodes = slower conduction and reduced contractility.
- work in SA pacemaker cells

50
Q

What are examples of non-vaughn Williams drugs used in treating arrhythmias?

A
  • Digoxin
  • Adenosine
51
Q

How does digoxin work as an anti-arrythmic drug?

A

Restores cardiomyocyte contractile function:
- Inhibits Na+/K+ ATPase
- Reversal of Na/Ca2+ exchanger
- Increases intracellular Ca levels

Normally, Na+ into cardiomyocyte and K+ out
But during action potential - increase in Na+ in and K+ out and
the Na/K+ ATPase restores this imbalance back to normal levels
BUT if the Na+/K+ atpase is inhibited with digoxin = increase in sodium ions in the cell
normally, Na/Ca exchanger exchanges Na+ in and ca2+ out, but if there is too much na+ in the cell, this activity is reversed (na out and ca in) = increased intracellular ca2+ in cardiomyocytes = increased force of contraction

52
Q

How does adenosine work as an anti-arrhythmic drug?

A

Binds to adenosine receptor (A-1 receptors on Atrium and SA and AV node) which decreases the firing of the SA node (pacemaker cells) = decreased conduction velocity and refractory period
- When adenosine binds to the adenosine-receptor which is coupled to the Gi receptor, Gi is released
- This inactivates adenylate cyclase = decrease in cAMP production = in chronotropy = extends the duration between action potential firing

53
Q

What can amiodarone (K+ channel blocker) do to thyroid?

A

Contains iodine so can cause hypo or hyperthyroidism

Exam 1- GI and CVD (43 decks)

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