Lectures 16, 17, 18, and 19 Flashcards
Which clotting factors do oral anticoagulants target?
Xa, IIa, VIIa, and IXa
What are some anticoagulants?
- Vitamin K antagonists (warfarin)
- Direct thrombin inhibitors (bivalirubin, dabigatran)
- Direct Xa inhibitors (rivaroxaban, apixaban)
What is the function of warfarin?
- Inhibits vitamin K1 2,3-epoxide reductase (prevents conversion of vitamin K epoxide to vitamin K, and conversion of vitamin K to vitamin K hydroquinone)
- Inactivates factors VII, IX, X, and II (thrombin)
What are consequences of warfarin action?
- Inhibits reduction of vitamin K
- Reduces gamma-carboxylation of clotting factors (reduces activity of clotting factors)
- Decreases production of new and active clotting factors II, VII, IX, and X
What is the function fo gamma-carboxyl glutamate?
Calcium chelator
Does warfarin have any effect on existing carboxylated clotting factors?
NOOO, they still remain active
How long does it take for warfarin to reach its full anticoagulant effect?
5 days b/c need to clear existing clotting factors
What are the uses of warfarin?
- Prevent venous thromboembolism
- Treat atrial fibrillation
- Prevent clotting w/ prosthetic heart valves
What are side effects of warfarin?
- Bleeding (major) – intracranial bleeding; incidence increases as tx duration and INR increase
- Skin necrosis (rare)
- Allergy
What is warfarin INR?
- International normalized ratio
- Ratio of px prothrombin time to a control (prothrombin time measures the activity of factors I, II, VII, and X)
What does the INR value mean?
- Normal untreated INR = 1
- Typical tx target INR = 2-3
- INR > 5 means overdose
What is needed to reach the target INR?
5 doses over 5 days
What is the antidote to warfarin?
Vitamin K or plasma (has clotting factors)
Which isomer of warfarin is more potent?
S
What is the S isomer of warfarin metabolized by?
CYP 2C9
What is the R isomer of warfarin metabolized by?
CYP 3A4, 1A2, and 2C19
Which drugs interact w/ warfarin?
- ASA (decrease platelet function)
- NSAIDs (GI ulceration)
- Antibiotics (decreased gut vitamin K synthesis)
- Cotrimoxazole (altered warfarin metabolism)
- Acetaminophen, doses over 2g/day (interference w/ vitamin K cycle)
Which drugs will interact w/ warfarin and increase bleeding?
- Metronidazole, macrolides, fluoroquinolones
- Azole antifungals, fluconazole, miconazole
- SSTI
- Clopidogrel, ASA
- NSAIDs, acetaminophen
What are some contraindications w/ warfarin?
- Foods rich in vitamin K
- Crosses placenta and causes birth defects; doesn’t cross into breast milk
What are the types of thrombin inhibitors?
- Direct or univalent (bind to active site of IIa; dabigatran, argatroban)
- Bivalent (bind to active site and exosite; lepiruidin, bivalirudin)
Bivalirudin is a ____ inhibitor of IIa
Non-competitive
What does bivalirudin bind to?
- IIa active site of fibrin-bound and free IIa to reduce platelet activation
- Exosite 1
What is bivalirudin used for?
As an anticoagulent in px undergoing percutaneous coronary intervention, w/ heparin induced thrombocytopenia
Bivalirudin is usually used w/ ___
ASA
What is dabigatran etexilate?
- Pro-drug for oral absorption (metabolized by esterases), but only absorbs in pH less than 3
- Direct thrombin (IIa) inhibitor (binds to thrombin active site and prevents conversion of fibrinogen to fibrin)
- Binds to free and fibrin bound thrombin => decreased platelet activation
Is the binding of dabigatran to thrombin reversible?
Yes
What are some drug interactions w/ dabigatran?
- Other drugs effecting clotting (warfarin, heparin, rivaroxaban)
- Anti-platelet aggregation (aspirin, NSAID, clopidogrel)
- Contraindicated in pregnancy and breast feeding
What are uses of dabigatran?
- Prevent venous thromboembolism following hip or knee replacement
- Prevent atrial thrombus and subsequent stroke in atrial fibrillation
- Alternative to warfarin (esp. if risk of stroke is high)
What are side effects of dabigatran?
- Dyspepsia
- Bleeding/hemorrhage
What is argatroban?
- Direct thrombin competitive inhibitor
- Given as continuous IV infusion
- Used in px w/ heparin-induced thrombocytopenia
What is AZD 0837?
- Direct thrombin competitive inhibitor
- Has to be in a pro-drug form for absorption
What does benzamidine do?
Broad spectrum inhibitor of most serine proteases; acts as a mimic for guanidine group of arginine
What is important about benzamidine when used in inhibitors?
- Fits in S1 site of IIa and Xa, producing potent inhibitors
- Charged at physiological pH, drastically reducing absorption and necessitating formation of a pro-drug
- Removal from IIa and Xa inhibitors reduces potency
What is rivaroxaban and apixaban?
- Direct competitive Xa inhibitor
- Used for prevention of venous thromboembolism in total knee or hip replacement surgery
- Tx of venous thromboembolism or deep vein thrombosis, pulmonary embolism, and prevention of recurrent DVT and PE
- Prevention of stroke and embolism in px w/ atrial fibrillation
What is the mechanism of clopidogrel, prasugrel, and ticagrelor?
- Glycoprotein GPIb binds collagen via von Willebrand factor
- Platelets “degranulate” releasing ADP
- ADP binds type 2 purinergic receptors (P2Y12) => intracellular release of Ca+2 via IP3 by activation of Gaq
- Ca2+ activates GP IIb/IIIa receptor complex, which binds fibrinogen => platelet aggregation
- Clopidogrel and prasugrel alkylate P2Y12 receptor irreversibly, which inhibits P2Y12 preventing platelet aggregation
- Ticagrelor is competitive antagonist of P2Y12 receptor
What is ticagrelor usually given w/?
ASA
What are the functions of H1 receptors around the body?
- Lungs/GI – smooth muscle contraction
- CNS – sleep wake regulation, vomiting
- Vasculature – increase vascular permeability
- Systemic – allergic response
What are the cellular effects of H1 receptors?
- Increase phospholipase C, IP3, DAG, and intracellular [Ca2+]
- Decrease K+ outflow
- Result = excitation
H1 receptors are G alpha ___
q
H2 receptors are G alpha __
s
H3 receptor are G alpha __
i
What are the functions of H2 receptors around the body?
- GI parietal cells – increase acid secretion
- CNS – memory
- Heart – increase force and heart rate (very minor)
What are the cellular effects of H2 receptors?
- Increase adenylate cyclase and cAMP
- Result = excitation
What are the functions of H3 receptors?
In CNS, auto-receptor, presynaptic inhibition, and blocks histamine release
What are the cellular effects of H3 receptors?
- Decrease cAMP and intracellular [Ca2+]
- Increase K+ outflow
- Result = inhibition
What is the function of histamine release?
To fight off parasitic infections
Which receptors primarily mediate the allergic histamine response?
H1 receptors
Which cells release histamine and in response to what?
Mast cells, in response to binding of allergens to IgE antibodies on mast cell surface
What effects are caused by histamine after it is released?
- Increased nasal secretion and vascular permeability
- Nasal congestion
- Clear rhinorrhea (won’t be clear in a sinus infection)
- Sneezing, itching, conjunctivitis
- Postnasal drip => coughing
- Wheals and flares (bumps w/ surrounding redness)
What is delayed-type hypersensitivity?
- Mediated by CD8 cells
- Manifests as a rash
- Takes 48h post-contact to develop
- Ex: exposure to poison ivy
- Treated w/ glucocorticoids; cannot be treated w/ antihistamines
What is anaphylactic shock?
- Causes life threatening bronchoconstriction w/ inability to breathe = medical emergency
- Treated w/ adrenaline
What is the predominant form of histamine?
Nt-tautomer (mono-cation form at physiological pH 7.4; charged N is needed for interaction w/ negatively charged aa in H1 and H2 receptors)
What are antihistamines?
H1 receptor antagonists
What are the 2 classes of H1 antagonists?
1) First gen or classical antihistamines - have affinity for many other receptor groups producing additional pharmacological effects and side effects
2) Second gen or “non-sedating” antihistamines - more specific for H1 receptors and have less side effects
Why do second gen antihistamines cause less sedation?
Less hydrophobic and can’t cross BBB
What are uses of first gen antihistamines?
- Tx of allergic response caused by release of histamine from mast cells
- Common cold (usually used for drowsiness)
- Hypnotics (ie for sleeping)
- Motion sickness