Extrinsic pathway is initiated by damage to a blood vessel which releases tissue factor

**Extrinsic pathway is more important for coagulation**

Protease that will digest 5a and 8a

Has to be activated (triggered by thrombomodulin)

Thrombomodulin itself is activated by thrombin (example of negative feedback)

Major adverse effect is bleeding, which is more common in elderly females and patients with impaired renal function

Thrombocytopenia

Long term treatment can lead to osteoporosis and spontaneous fractures

Can either be IV or SC (IV will have immediate onset)

Must monitor efficacy by partial thromboplastin time to maintain anti-coagulant activity within a safe range

Can be reversed by stopping and treatment and infusion with protamine sulfate, which combines with heparin

Prevention or treatment of a DVT

Acute MI: used in conjugation with thrombolysis or PCI 

Anticoagulation in pregnant women 

Fragments of standard heparin produced by enzymatic digestion

Weaker activity on ATIII but still inhibits Factor 10a

Fewer bleeding side effects

Usually given SC once a day

Very effective in preventing DVT post surgery

Generally preferred over heparin because it is more convenient, eliminates need for aPTT monitoring, and reduces risk associated with IV injection

Although more expensive per dose, long term outcomes are cheaper

Factor 10 inhibitor

Synthetic pentasacharide is indirect Factor 10a inhibitor WITHOUT direct effect on thrombin

Delivered subcutaneously

Licensed for prevening DVT and acute pulmonary embolism

Small molecule orally active Factor 10a inhibitor

Approved for non-valvular atrial fibrillation

Approved for prophylaxis against venous thromboembolism associated with knee and hip replacement surgery

Small molecule orally active Factor 10a inhibitor 

Stroke prophylaxis in patients with non valvular atrial fibrillation 

Derivative of hirudin used in prevention of post-op development of venous thromboembolism, and some studies have demonstrated superiority over low MW heparins

Delivered subcutaneously

Oral thrombin inhibitor

Prodrug - metabolized to dabigatran in a P450 INDependent fashion

Reduced risk of bleeding compared to warfarin 

Approved for patients with atrial fibrilliation for stroke prevention

Pregnancy category C drug 

Analogs of Vitamin K 

Block gamma carboxylation of gluatamate residues (2,3,9,10) by inactivating epoxide reductase 

Results in proteins that are inactive in the coagulation cascade

8-12 hour delay in onset of effects; 1-3 day delay in appearance of peak effects 

Treatment should start with a small daily dose to obtain optimal adjustment of prothrombin time (measured as INR - Ptpt/Ptnormal)

Effects can be reversed by stopping administration and treating with Vitamin K or Factor 9 concentratres (Proplex, Konyne 80)

Atrial fibrillation (atria going crazy and blood will pool which might form a thrombus)

Prosthetic heart valves

Teratogenic, so is contraindicated in women who are pregnant or contemplating pregnancy (LMW heparin should be used)

A number of agents affect it

Effects can be pharmacokinetic (altering metabolism)

Effects can be pharmacodynamic (altering activity)

Protein (not protease) from Streptococcus that activates plasminogen to convert plasminogen into plasmin

Not as effective as tPA in treatment of acute mI, since streptokinase must be infused over a span of 30-60 minutes

Complex of plasminogen and streptokinase that has been acetylated to protect active site

Once in plamsa, the protecting group comes off, releasing the active complex - plasminogen will convert plasminogen into plasmin

Still not as effective as tPA in dissolving clots because streptokinase must be infused over a 30-60 minute period

Protease that preferentially activates plasminogen bound to fibrin, which in theory, confines fibrinolysis to clots 

Urokinase has similar activity 

Variant forms such as tenecteplase (3 amino substitution of tPA) has better fibrin specificity and reduced plasma clearance - starting to replace tPA

delivered as an IV bolus, providing immediate action

3 amino acid substitution of tPA

has more specificity for fibrin and reduced plasma clearance so beginning to replaced tPA

Multiple pulmonary emboli, central DVT, management of acute MI, treatment with fibrinolytic agents within the first hour of an MI (GOLDEN HOUR) dramatically decreases mortality 

Effectiveness decreases as the time between MI and treatment until no significant difference is observed after 12 hours

This is where tPA has greatest advantage over streptokinase

Prevents TXA2 synthesis (prevents platelet aggregation)

Low doses (80mg/day) prevents first and subsequent MI (CAD, age, smoker, high cholesterol, HTN)

Irreversible inhibitor of COX-1 

High dose of aspirin (320 mg) at beginning of MI markedly reduces mortality 

May not be tolerated by GI irriation (less PGE2 (mucous secretion))

Some patients may be resistant to aspirin (5-20%)

Recent studies have shown that low dose aspirin reduces mortality associated with a number of cancers if taken > 5 years

Inhibits ADP mediated platelet aggregation

Irreversible inhibitors of ADP binding to P2Y12 receptors (useful for patients that can't tolerate aspirin)

Clopidogrel (plavix) prodrug metabolized to active form by CYP2C19

Combo with aspirin greater than two alone in preventing MI reocclusion 

Prasugrel (effient) is more potent than clopidogrel but has a higher risk of bleeding (not dependent on CYP2C19)

More potent than clopidogrel and has a higher risk of bleeding

Although it is a prodrug, not dependent on CYP2C19, so not affected by CYP2C19 polymorphisms

Targets platelet receptors for integrin and other aggregating substances

All are delivered IV and are combined with aspirin and anticoagulant therapy 

Mouse/human chimeric antibody directed against 2b and 3a

receptors

Used in cnojuction with aspirin or heparin in angioplasty

Nonpeptide peptidomimetic that inhibits fibrin binding to the GP 2b/3a receptor preventing aggregation 

It binds at a different site than eptifibatide, but has same effect

Main use is in high risk acute coronary syndrome or PCI

Characterized by progression of stable angina to repeated episodes, even at rest

Usually due to atheroscleorit plaque rupture

Very often a precursor to acute MI

Angina of effort (stable): try to decrease work of heart through systemic vasodilation

Unstable angina: reduce cardiac work as well as thrombogenesis

Variant angina: pharmacological agents can be used to reverse coronary vasospasm

increase cGMP - dephosphorylates MLCK (like organic nitrates)

decrease intracellular calcium (calcium channel blockers)

Increasing potassium permeability (K channel openers)

increase cAMP (inactivates MLCK faster - not used for angina due to effects on HR and contractility)

Release NO at target tissues which activates guanylyl cyclase which elevates cGMP -- 

dilates large coronary arteries and arterioles (redistributes blood flow from epicardial to endocardial regions)

MAIN EFFECT IS VENODILATION - reduces preload and ventricular filling, which turn reduces myocardial oxygen demand

Hepatic organic nitrate reductase - significant first pass metabolism

Isosorbide 5-mononitrate is not subject to first pass metabolism, so it can be delivered orally, and has a longer duarion of action than isosorbide dinitrate and nitroglycerin 

Sublingual and slow release buccal administration attains therapeutic levels, while bypassing hepatic system

Inhalation of volatile nitrites (like amyl nitrite) also bypasses hepatic system

Repeated administraiton leads to loss of effectiveness

Tolerance is apparent after use of long acting, slow release preparations or infusions of several hours or more

Large degree of CROSS TOLERANCE between nitrates

Withold for 8-10 hours to restore sensitivity 

Dihydropyridines (nifedipine, amlodipine, feldipinie)

non DHPS: verpamil and diltiazem

decrease myocardial contracticle force (verpamil, diltiazem)

decreased arterial tone and systemic vascular resistance (all)

Stable angina (all CCBs)

Unstable angina (verpamil and diltiazem)

Hypertension (all CCBs)

Supraventricular tachycardia (verpamil and diltiazem)

Hypotension
Bradycardia

Decreased cardiac contractility  

Are not vasodilators - decrease HR and contractility to reduce oxygen demand

All b blockers are EQUALLY EFFECTIVE as anti anginals

Often used in conjunction with DHP Calcium channel blockers to offset some of the side effects of these agents - mainly the reflex tachycardia (do not use with verapamil or diltiazem)

Approved by FDA in 2006 for patients who have not responded to other anti-anginal agents 

Thought to inhibit late Na current which increases Ca transport out of the cell (also reduces Na entry into the cell)

Net effect is improved diastolic function and decreased oxygen demand

Due to action on cardiac channels, should be avoided in QT prolongation patients

Main indication is for treatment of stable angina in patients who do not respond to other treatments 

Hospitalize/bed rest, b blockers, antiplatelet and anticoagulant (heparin) fibrinolytic agents have been shown to be ineffective as well as calcium channel blockers

Longer term: use lipid lowering drugs like the statins to reduce further plaque formation

Underlying cause is a reversible coronary vasospasm

Usually responsive to nitrates and calcium channel blockers