3. Drugs that affect Coagulation
■ Thrombosis may occur in both arteries and veins
■ Arterial thrombi cause disease by obstructing
blood flow which can result in tissue ischemia or
death
■ Venous thrombosis is associated with venous
stasis. A venous thrombus is less cohesive than
an arterial embolus so venous emboli more
prevalent
4. Hemostasis
■Hemostasis is the prevention or stoppage of
blood loss from an injured blood vessel.
■Process involves vasoconstriction, formation
of a platelet plug, activation of clotting factors
and growth of fibrous tissue into the blood
clot making it more stable.
5. Antiplatelet Drugs
■ Arterial thrombi are composed primarily of platelets
■ Antiplatelet drugs act by inhibiting platelet
activation, adhesion, aggregation, or procoagulant
activity.
■ Include drugs that block platelet receptors for
thromboxane, ADP, glycoprotein IIb/IIIa and
phosphodiesterase inhibitors
6. Platelet Inhibitors
■ Inhibit the aggregation of platelets
■ Indicated in progressing MI, TIA/CVA
■ Side Effects: uncontrolled bleeding
■ No effect on existing thrombi
7/17/23 6
7. Thromboxane A2 Inhibitors
■ Work by inhibiting synthesis of prostaglandins. TA
inhibitors work by acetylating cyclooxygenases, the
enzyme in platelets that synthesizes thromboxane A2
(which causes platelet aggregation).
■ ASA (aspirin) is example. It affects the platelets for the
life of the platelet.
■ NSAIDs not so useful as action wears off as drug
wears off
8. Adenosine Diphosphate Receptor
Antagonists
Ticlopidine
■ Inhibit platelet aggregation by preventing ADP-
induced binding between platelets and fibrinogen.
This reaction inhibits platelet aggregation irreversibly
and persist for the lifespan of the platelet (9-10
days)
■ Indicated in TIAs
■ Adverse effects-neutropenia, diarrhea, skin rashes
9. Adenosine Diphosphate Receptor
Antagonists
Clopidogrel
■ Fewer side effects than ASA or Ticlopidine
■ indicated for patients with atherosclerosis
for reduction of MI, stroke and vascular
death
■ Does not need reduction in those with renal
problems
10. ■ Used with aspirin and heparin and is contraindicated in
clients who have recently received oral anticoagulants or
IV dextran.
■ Other contraindications include active bleeding,
thrombocytopenia, history of stroke, surgery or trauma
within past 6 weeks, uncontrolled hypertension or
hypersensitivity.
11. Miscellaneous
■ Dipyridamole inhibits platelet aggregation, but
mechanism is unclear
■ Used for prevention of thromboembolism after
cardiac valve replacement and is given with
Coumadin
12. Anticoagulants
■ Interrupt clotting cascade at various points
– No effect on platelets
■ Heparin & LMW Heparin (Lovenox®)
■ warfarin (Coumadin®)
7/17/23 12
13. Heparin
■ Endogenous
– Released from mast cells/basophils
■ Binds with antithrombin III
■ Antithrombin III binds with and inactivates excess
thrombin to regionalize clotting activity.
– Most thrombin (80-95%) captured in fibrin mesh.
■ Antithrombin-heparin complex 1000X as effective as
antithrombin III alone
7/17/23 13
14. Heparin
■ Measured in Units, not milligrams
■ Indications:
– MI, PE, DVT, ischemic CVA
■ Antidote for heparin OD: protamine sulphate.
– MOA: heparin is strongly negatively charged.
Protamine is strongly positively charged.
7/17/23 14
15. Low Molecular Weight Heparins
■ Given subcutaneously in abdomen and do not
require close monitoring of blood coagulation tests
■ Still should follow platelet counts
■ Dalteparin
■ Enoxaparin
16. warfarin (Coumadin®)
■ Prothrombin (II), Proconvertin (VII), Christmas factor
(IX) and Stuart-Prower factor (X) all require vitamin
K dependent enzymes for their synthesis.
■ Warfarin competes with vitamin K in the synthesis
of these enzymes.
■ Depletes the reserves of clotting factors.
■ Delayed onset (~12 hours) due to existing factors
7/17/23 16
17. Warfarin
■ Dosage reduction in patients with biliary tract
disorders, liver disease, malabsorption syndromes,
and hyperthyroidism. These conditions increase
anticoagulant drug effects by reducing absorption of
vitamin K or decreasing hepatic synthesis of clotting
factors
■ Has multiple, multiple drug interactions
■ Counteract with vitamin K
18. Other anticoagulants
■ Danaparoid — low molecular weight, heparin-
like drug. Used in management of hip surgery,
ischemic stroke or in those who cannot take
heparin. Does not contain heparin.
■ Lepirudin — used as heparin substitutes
■ Fondaparinux –binds to clot bound factor Xa,
inhibits thrombin productions
20. Thrombolytics
■ Given to dissolve thrombi
■ Stimulate conversion of plasminogen to plasmin, an
enzyme that breaks down fibrin (the framework of a
thrombus)
■ Used in severe thromboembolic disease such as MI,
PE and ileofemoral thrombosis
21. Thrombolytics
■ Goal is to re-establish blood flow and prevent tissue
damage
■ Also used to dissolve clots in arterial or venous cannulas or
catheters
■ Must obtain baseline INR, aPTT, platelet count and
fibrinogen
■ Will monitor labs 2-3 hours after thrombolytic treatment is
instituted to determine efficacy
22. Thrombolytics
■ Directly break up clots
– Promote natural thrombolysis
■ Enhance activation of plasminogen.
■ Reduce mortality from MI
■ Less systemic bleeding risk with Alteplase and other
newer thrombolytics as compared with Streptokinase.
■ However, haemorrhagic stroke risk with Alteplase is
higher than Streptokinase.
■ alteplase (tPA®, Activase®)
■ streptokinase (Streptase®)
■ anistreplase (Eminase®)
■ reteplase (Retevase®)
■ tenecteplase (TNKase®)
7/17/23 22
23. Drugs Used to Control Bleeding
■ Aminocaproic acid and tranexamic acid are used to
stop bleeding caused by overdoses of thrombolytic
agents
■ Aprotinin indicated in patients undergoing CABG .
Inhibits breakdown of blood clotting factors.
24. Cholesterol Metabolism
■ Cholesterol important component in membranes and as hormone
precursor
■ Synthesized in liver
– Hydroxymethylglutaryl coenzyme A reductase
– (HMG CoA reductase) dependant
■ Stored in tissues for latter use
■ Insoluble in plasma (a type of lipid)
– Must have transport mechanism
7/17/23 24
25. Cholesterol
■ Risk of Coronary artery disease linked to LDL levels
■ LDLs are deposited under endothelial surface and
oxidized where they:
– Attracts monocytes -> macrophages
– Macrophages engulf oxidized LDL
■ Vacuolation into ‘foam cells’
– Foam cells protrude against intimal lining
■ Eventually a tough cap is formed
– Vascular diameter & blood flow decreased
7/17/23 25
26. Overview of cholesterol panel
Total cholesterol
Desirable-less than 200
Borderline high—200-239
High—240 or greater
LDL
Desired <100
Above optimal—100-129
Borderline high—130-159
High-160-189
Very highà190
27. Overview cont.
HDL
■ High >60
■ Low <40
Triglycerides
Normal—less than 150
Borderline high—150-199
High--200 to 499
Very high—500 or above
28. Dyslipidemia
■ Associated with atherosclerosis and numerous
pathophysiologic effects
■ Elevated total cholesterol, high LDL and low HDL are
all risk factors for CAD
■ TG indicated excessive caloric intake; excessive
proteins and carbohydrates are converted to TG and
obesity
30. Dyslipidemia cont.
■ High dietary intake also increases the conversion of
VLDL to LDL cholesterol, and high dietary intake of
TG and saturated fat decreases the activity of LDL
receptors and increases synthesis of cholesterol.
31. Types of Lipoproteins
■ LDL—unfavorable type. Transports 75% of serum cholesterol
to peripheral tissues and the liver. High levels are
atherogenic
■ VLDL—contains 75% TG and 25% cholesterol. Transports
endogenous TG to fat and muscle cells.
■ HDL—favorable type. This LP transports cholesterol back to
the liver for catabolism and excretion.
33. Drug Therapy
■ Based on the type of dyslipidemia and its severity
■ Classes of agents include: HMB-CoA reductase
inhibitors or “statins”, fibrates, bile acid
sequestrants and niacin in different forms
■ Lovaza (omega-3 fatty acid)
■ Ezetimibe (Zetia®)
35. ■ Statins [Atorvastatin, Rosuvastatin, Simvastatin]
Compete to inhibit HMG-CoA reductase, rate limiting enzyme in the de novo
synthesis of cholesterol
■ Bile acid-binding resin [Cholestyramine, Colestipol]
– Increases bile acid excretion. Lowers LDL
■ Fibrates [Clofibrates, Gemfibrozil]
– Inhibits peripheral lipolysis, decreases hepatic uptake of free fatty acids;
lowers secretion of VLDL
■ Niacin
– niacin inhibits the lipolysis of TG by hormone-sensitive lipase
■ Ezetimibe
– Inhibits cholesterol absorption
7/17/23 35
36. HMG-CoA reductase inhibitors or “statins”
■ Inhibit an enzyme (hydroxymethylglutaryl-coenzyme
A reductase) required for hepatic synthesis of
cholesterol
■ Decrease serum cholesterol, LDL, VLDL and TG
■ Reach maximal effects within about 6 weeks
37. Statins cont.
■ Drugs also reduce C reactive protein, associated
with inflammation and development of CAD
■ Undergo extensive first pass metabolism
■ Metabolism occurs in liver
38. Statins cont.
■ Adverse effects include diarrhea, rashes,
headaches, constipation, hepatotoxicity and
myopathy.
■ Should obtain baseline LFTs and then at 6 and 12
weeks after starting then every 6 months
■ If serum aminotransferases increase to more than
3x normal, should be reduced.
39. Statins cont.
■ Do not take with grapefruit juice
■ Pregnancy category X
■ Examples: Lipitor (atorvastatin), Pravachol
(pravastatin), Zocor (simvastatin), Lescol
(Fluvastatin)
40. Bile Acid Sequestrants
■ Bind bile acids in the intestinal lumen. This causes
the bile acids to be excreted in feces and prevents
their being recirculated to the liver. Thus, the liver
will use cholesterol to produce bile acids thus
decreasing serum levels.
41. Bile Acid Sequestrants
■ Especially lower LDL
■ Examples are: Questran (cholestyramine) and
Welchol (colesevelam)
■ Often used with patients already on a statin
■ Long term use can affect absorption of folate,
Vitamins A,D,E,K
42. Fibrates
■ Tricor (fenofibrate)
■ Lopid (gemfibrozil)
■ These drugs increase oxidation of fatty acids in liver
and muscle tissue thus decreasing hepatic
production of TG, VLDL and increase HDL.
■ Most effective drugs for reducing TG.
43. Fibrates cont.
■ Can cause hepatotoxicity
■ Main side effects include diarrhea, GI discomfort,
cause gallstones, interact with Coumadin
44. Niacin (nicotinic acid)
■ Decreases both cholesterol and triglycerides
■ Bottom line—decreases hepatic synthesis of TG and
secretion of VLDL (which leads to decreased
production of LDL)
■ Need high doses for efficacy
45. Niacin
■ Side effects include flushing, pruritus, gastric irritation. May
cause hyperglycemia, hyperuricemia, elevated hepatic
aminotransferase enzymes and hepatitis.
■ Can reduce flushing by starting with low doses, taking dose
with meals, and taking ASA 325mg thirty minutes before
taking dose
■ More effective in preventing heart disease when used in
combination with another dyslipidaemic agent such as a
bile acid sequestrant or a fibrate.
46. Others
■ Ezetimibe (Zetia) Inhibits absorption of cholesterol
from small intestine
■ Don’t give with cholestyramine (Questran)
47. Important reminders
Risk factors for thromboembolism
1. Obesity
2. MI
3. Atrial fibrillation
4. Prosthetic heart valves
5. Atherosclerotic heart disease
6. Oral contraceptives/Hormone replacement therapy
7. History of DVT or PE
8. Cigarette smoking
9. Immobility
49. ■ Stroke occurs when the supply of blood to the brain is either interrupted or
reduced.
■ There are three main kinds of stroke; ischemic, hemorrhagic and Transcient
ischaemic attacks.
■ Ischaemic stroke- caused by blockages or narrowing of the arteries that
provide blood to the brain, resulting in ischemia. Most common (in 80%).
■ Hemorrhagic stroke is caused by arteries in the brain either leaking blood or
bursting open.
– Hypertension, trauma, blood-thinning medications and aneurysm
(weaknesses in blood vessel walls).
■ TIAs are different from the aforementioned kinds of stroke because the flow
of blood to the brain is only briefly interrupted. TIAs are similar to ischemic
strokes in that they are often caused by blood clots or other debris.
7/17/23 49
50. Types of stroke
Intracerebral haemorrhage
(30%)
Ischaemic (65%) Subarachnoid
haemorrhage (5%)
• This type of stroke is
caused by a blockage in an
artery that supplies blood to
the brain
• The blockage reduces the
blood flow and oxygen to
the brain, leading to damage
or death of brain cells
• An emergency condition in
which a ruptured blood
vessel causes bleeding
inside the brain.
• High blood pressure and
trauma are two leading
causes.
• Bleeding in the space
between the brain and the
tissue covering the brain.
• Subarachnoid haemorrhage,
a medical emergency, is
usually from a bulging blood
vessel that bursts in the
brain (aneurysm).
51. Risk Factors of Stroke among West Africans
ISCHEMIC STROKE
■ Hypertension
■ Dyslipidaemia
■ Diabetes Mellitus
■ Raised Waist-to-Hip ratio
■ Cardiac Disease
■ Physical Inactivity
■ Stress
■ Table added salt
■ Regular Meat consumption
■ Low consumption of green leafy
vegetables
HAEMORRHAGIC STROKE
• Hypertension
• Dyslipidaemia
• Diabetes Mellitus
• Cigarette smoking
• Stress
• Table added salt
• Regular Meat consumption
• Low consumption of green
leafy vegetables
52. Management of Ischemic Stroke
■ Supportive Care
■ Management of BP (<180/110 mm Hg)
■ Fluid –0.9% Saline (to maintain hydration and electrolyte balance; in excess can cause
brain swelling. 5% dextrose or half NS avoided due to increased ICP risk)
■ Hyperglycaemia(> 40% of cases) (can be managed with insulin to prevent worsening
clinical outcome and increased mortality)
■ Fibrinolysis with rTPA
■ Acute angioplasty/stenting
■ Management of complications – DVT, sepsis
■ Rehabilitation
■ Citicoline (Somazina) believed to improve clinical outcome following
ischemic stroke (Decreases death rate and disability post-CVA)
53. Management of Ischemic Stroke
Antiplatelet/Anticoagulant therapy
■ Aspirin 300mg for 15 days or 150 mg for 30 days followed by 75 mg
for life
■ Clopidogrel if intolerant of Aspirin
■ Aspirin + Dipyridamole
■ Aspirin + Clopidogrel combination for TIA or mild strokes
■ Anticoagulant therapy for Cardioembolic strokes (Atrial fibrillation)
54. Management of Ischemic Stroke
Acute Thrombolytic Therapy
■ IV tissue Plasminogen Activator: 0.9 mg/kg (with caution)
Criteria for thrombolysis:
■ < 3 hr from onset
■ Intracerebral haemorrhage excluded by imaging
■ SBP < 185; DBP < 110 mm Hg
■ Platelets > 100,000
■ Patient not on anticoagulants, no recent surgery or GI bleeding; no seizures at onset
55. Management of Intracerebral Haemorrhage
■ Rapid neuroimaging
■ Intubation if necessary (CPR)
■ Emergency haematoma evacuation
■ External ventricular drainage
■ Management of raised ICP
■ BP and hyperglycaemia management
■ Reversal of coagulopathy
56. Management of Subarachnoid haemorrhage
■ Clipping
■ Endovascular coiling to limit blood flow into aneurysm
■ Use of Tranexamic Acid/Aminocaproic acid to prevent rebleeding in the
acute phase (<72 hrs.)
■ Management of raised ICP
■ BP management
■ Anticonvulsants to relieve pain and seizures
■ Prevention of vasospasms (e.g. Nimodipine, Clazosentan)
■ Simvastatin and Mag. Sulphate are contraindicated (no benefits in
decreasing incidence of vasospasm)
57. DVT Prophylaxis after ischaemic stroke
■ SC administration of anticoagulants is recommended for
treatment of immobilized patients to prevent DVT
■ Use of intermittent external compression devices is
reasonable for treatment of patients who cannot receive
anticoagulants
58. DVT Prophylaxis after haemorrhagic stroke
■ After documentation of cessation of bleeding, low-
dose subcutaneous LMW Heparin is probably safe in
patients with ICH
■ It may be considered on an individual basis for
patients with hemiplegia after 3 to 4 days of stroke
onset
