Download Pharmacotheraputics

Hematology Pathophysiology: Integrative Pharmacology (Ibrahim)
BENIGN HEMATOLOGY:
Oral Anticoagulants:

Warfarin:
MOA: inhibits vitamin K epoxide reductase leading to inhibition of reduction of vitamin K, which is required for
carboxylation (and activation) of factors II, VII, IX and X, as well as proteins C, S and Z
o Inhibits the above factors
o Inhibition of II, VII, IX, and X prevents extension and propagation of existing clots
o Inhibition of protein C and S (natural anticoagulants) leads to an initially hypercoaguable state

Depletion of C and S occurs before II, VII, IX and X (shorter half lives)

As a result, patients started on warfarin for acute DVT event require bridge therapy with
another anti-coagulant (ie. LMWH, UFH)
 Note that with AFIB, you can start on warfarin alone
Warfarin Genetic Testing Available: tests may be helpful in unusual patients prior to starting the drug; however,
these are not widely used because it is hard to identify such patients
o VKOR Deficiency: would result in enhanced drug effects
o CYP2C9 Polymorphisms: processes warfarin

Increased activity  decreased drug levels

Decreased activity  increased drug levels (excessive anti-coagulation)
Monitoring:
o PT Testing: measure factors II, VII, IX and X (as well as factor V)
o INR (International Normalize Ratio): accepted standard for warfarin monitoring (derived from PT)

Reason for Use: standardizes the interpretation of anticoagulation intensity across hospitals

Goal INR with Warfarin Therapy: 2-3
 Above: over-coagulation
 Below: under-coagulation

Normal Individuals INR: <1.3
 Note that INR may also be elevated in patients that are not taking warfarin
o Liver disease (defective coagulation factor production)
o Long term antibiotics and illness (deplete vit K producing gut bacteria)
o Monitoring INR:

Venipuncture: hospitals

Point of Care Testing: anti-coagulation clinics and primary care offices
Pharmacokinetics:
o Slow Onset of Action: 3-5 days (another reason for bridge therapy with LMWH/UFH)
o Half Life: 36-42 hours
o No Renal Clearance: safe in patients with compromised renal function
o Vitamin K Antagonism: high vitamin K antagonizes warfarin (ie. decreases INR)

Diet related sources (ie. leafy green vegetables)

Over the counter products (ie. calcium citrate)
Drug Interactions: TONS*
o Metabolic Inducer: DECREASE warfarin levels

Rifampin
o Metabolic Inhibitor: INCREASE warfarin levels

Amiodarone

Quinolones

TMP/SMX (Bactrim)
o Acetminophen: potentiates inhibition of components of vitamin K cycle

Pharmacodynamic interaction (additive effects with warfarin)

By itself, acetaminophen decreases vitamin-K dependent factors in the liver
Warfarin and Surgery:
o Risk of thromboembolism off of warfarin for only 2 days can be as high as 1%, depending on risk
factors for clotting
o Consider stopping warfarin if a patient is going to undergo high bleeding risk surgery:

At least 5 days off of drug before factor II has had enough time to be replenished

INR of <1.6 is cut-off for surgery
o In some emergency situations (ie. ruptured aortic aneurysm), immediate anticoagulation is required
-
-
Side Effects:
o Bleeding:

ANTIDOTE= VITAMIN K*

Risk Factors:
 Older age
 Concomitant medication
o Pharmacokinetic (ie. TMP-SMX increasing warfarin levels)
o Pharmacodynamic (ie. clopidogrel’s additive effects)
 Intensity of anticoagulation
o Some patients require higher INR range (ie. mechanical valves)
o These patients have higher risk of bleeding due to increased INR
 Length of anticoagulation
o Longer you are on it, the higher your chance of bleeding

Worst Scenario: CNS bleeding (subdural/epidural hematomas, intracranial hemorrhages)

Management of Bleeding and High INRs in Patients on Warfarin:
 Elevated INR WITHOUT Bleeding:
o INR <5: lower or withhold dose
o INR 5-8.9:

Hold 1 or 2 doses, or

Hold a dose and give vitamin K PO, or

Give large dose of vitamin K PO if rapid reversal is required

Give additional vitamin K if INR remains high
o INR ≥9:

Hold warfarin therapy and give vitamin K PO

Give additional vitamin K if INR remains high
 Elevated INR WITH Bleeding:
o Serious Bleeding:

Hold warfarin and give vitamin K by IV; supplement with FFP,
PCC or rVIIa

Vitamin K may be repeated every 12 hours based on INR
o Life Threatening Bleeding:

Hold warfarin therapy and give FFP, PCC or rVIIa supplemented
with vitamink K by IV

Repeat if necessary based on INR
o Purple Toe Syndrome:

Basics: painful, tender, well demarcated red/hemorrhagic plaques with an erythemetous rim
 Usually in the lower extremities

Pathophysiology: unknown
 Possibly due to protein C deficiency
o Inherited or acquired (ie. oral contraceptives)
 Possibly due to high warfarin loading doses dropping protein C quickly, leading to
pro-thrombotic state
 Frequently seen in patients on warfarin for DVT (not as much for AFIB)

Incidence: uncommon

Onset: 1-10 days after warfarin initiation

Management: STOP WARFARIN ASAP
Barriers to Optimal Use:
o Need for repeated blood monitoring (narrow therapeutic window)
o Difficulty achieving optimal INR (only 60% of patients achieve INR of 2-3)
o Slow onset and offset of action (requires bridging therapy)
o Complicated dosing regimens
o Drug and dietary interactions
o Compliance (affected by all of the above)
o Theoretical increased risk for osteoporosis (vit K antagonists appear to inhibit vit K-dependent proteins
in the bones; not considered in clinical decisions)


Dabigatran:
MOA: direct thrombin inhibitor
o Binds only to the active site of thrombin (other parenteral DTIs bind exosites as well)
o Inactivates fibrin-bound and unbound (free) thrombin
o Results in disruption of coagulation
Monitoring: NO INR monitoring needed
o aPTT provides a qualitative measure (ie. is the drug in the body or not)
Use:
o Non-Valvular AFIB: approved for reduction of stroke risk and systemic embolism

Most beneficial to patients with:
 Poor INR control
 Inability to comply with INR monitoring
 Challenges to medication adherence
Advantages Over Warfarin:
o Significantly shorter onset of action

However, also a quick offset and therefore if a patient misses a dose, protection is lost faster
o More predictable pharmacokinetics
o Fewer DDIs

Although it is a substrate for p-glycoprotein
o Fixed dosage

However, may not be appropriate for patients with extremes of body weight (ie. <50kg)
o Reduced risk for intracranial bleeding
o No need for therapeutic monitoring

However, this makes it harder to detect overexposure to dabigatran
Disadvantages Compared to Warfarin:
o NO ANTIDOTE!

Since dabigatran inhibits (instead of depletes) thrombin, PCC and other coagulation factor
replacement will not reverse dabigatran’s anticoagulant effect

Can use dialysis to remove the drug (but not available everywhere)
o Renally eliminated

Need to discontinue drug sooner before surgery (3-5 days instead of 1-2 days prior)

Be careful with use in elderly patients
o GI intolerance (may be due to inactive ingredient tartaric acid found in capsule)
o More life-threatening bleeding? (post-marketing reports of serious bleeding events)
Rivaroxaban:
MOA: direct factor Xa inhibitor
Monitoring: NONE
Use:
o Non-valvular AFIB: prevention of stroke and systemic embolism
o Knee/Hip Replacement Surgery: prevention of DVT
DDIs: more than dabigatran*
o Substrate for P-glycoprotein (like dabigatran)
o CYP450 3A4 inhibitors/inducers
Advantages Compared to Warfarin:
o Fixed dose
o No INR monitoring
o Quick offset
Disadvantages Compare to Warfarin:
o NO ANTIDOTE
o Renally eliminated
Comparison to Dabigatran: unclear if there is a benefit over dabigatran
Parenteral Anticoagulants:

Heparins:
Unfractionated Heparin (UFH):
o MOA: binds to ATIII to induce a conformational change and allow it to become a rapid inhibitor

Inhibits factors Xa, IIa, IXa and XIa

Large molecule that is cleared from the body faster
-

Low Molecular Weight Heparin (LMWH):
o Agents:

Enoxaparin

Dalterparin

Tinzaparin
o MOA: binds to ATIII to induce a conformational change and allow it to become a rapid inhibitor

Inhibits mostly factor Xa, and to a lesser extent, factor IIa

Shorter molecule and is therefore cleared from the body slower
o Advantages Over UFH:

Longer duration of action (slower clearance from the body)

100% bioavailability

Predictable pharmacokinetics (does not bind plasma proteins)
 No need for PTT monitoring

Less risk of HIT

Less risk of osteoporosis when given long-term
Clinical Indications for UFH/LMWH:
o Acute coronary syndromes
o Initial treatment of DVT and PE

Bridge therapy for warfarin (~5 days)

Due to warfarin’s slow onset of action AND protein C depletion with first time use
o DVT prophylaxis following abdominal and orthopedic surgeries
o General DVT prophylaxis in medically ill patients
Monitoring:
o aPTT for UFH: depletion of factors XIa, IXa, Xa and IIa (rarely for LMWH)

Decreased aPTT: under anti-coagulation

Increased aPTT: over anti-coagulation
o aPTT Measures the Intrinsic Pathway: may also have increased aPTT in conditions other than heparin
therapy

Liver disease

DIC

Lupus anticoagulant
Side Effects:
o Bleeding:

Risk Factors: recent surgery or trauma

Heparin and Surgery: if going for procedure with high bleeding risk
 UFH: stop 4-6 hours before
 LMWH: stop 12-24 hours before

Protamine: antidote for UFH; only partially effective for LMWH (~60%)
o Heparin Induced Thrombocytopenia (HIT):

Basics: drop in platelet count but pro-thrombotic state due to platelet hyperreactivity
 Platelets are low due to consumptive coagulation process
 Triggered by IgG Abs against platelets (triggered by UFH; less often by LMWH)

Presentation: patients present with venous and arterial thrombosis

Onset:
 Immediate in patients pre-exposed to heparin
 Delayed (>7-10 days) in first exposure cases

LMWH and HIT: although there is a decreased incidence of HIT with LMWH, you cannot use
LMWHs in patients with a history of HIT (potential cross reactivity)

Other Options for Anticoagulation:
 Direct thrombin inhibitors
 Indirect factor X inhibitors
Indirect Factor X Inhibitors:
Fodaparinux:
o MOA: indirect inhibitor of factor X
o Indications:

Treatment and Prevention of DVTs/PE: alternative to LMWHs and UFH

HIT: not officially approved, but may be used
o Side Effects: bleeding
o

Other Information:

Once a day dosing (longer duration of action)

No monitoring required

Renal excretion
Direct Factor II/Thrombin Inhibitors (Parenteral):
Agents: all have short half lives (minutes-hour)
o Lepirudin

Management of HIT

Renal excretion
o Bivalrudin

Use in patients with HIT or HITTS undergoing PCI

Enzymatic degradation
o Argatroban

Mangement of HIT

Use in patients with HIT undergoing PCI

Hepatic excretion
Use:
o HIT: standard first line treatment
Side Effects:
o Bleeding:

Risk Factors:
 Renal dysfunction (lepirudin- renally excreted)
 Liver dysfunction (argatroban- hepatic excretion)
Monitoring: aPTT
Factor VII:

Use:
Hemophilia A and B: proven benefits
Other Bleeding Conditions: often used off-label in severe bleeding, although evidence is unclear
o Trauma
o Cirrhosis
o Pulmonary hemorrhage
o Cerebral hemorrhage

Monitoring Parameter: PT/INR (?)
Tricky because PT/INR does not account for tissue-factor independent effects
PT may be normal but it does not mean that homeostasis has been achieved

Side Effects:
Thrombosis: arterial and venous
o Occurs within 24 hours of drug administration in 50% of patients
o More likely associated with NON-HEMOPHILIAC bleeding than hemophiliac bleeding

Non-hemophiliac bleeding have platelets activated all over (as opposed to localized)

Widespread platelet activation leads to higher THROMBIN BURST even outside the site of
injury  procoagulant state
Anti-Fibrinolytics:

Agents:
Aminocaproic acid
Tranexamic acid

MOA: prevent activation of plasminogen to plasmin (blocks lysine binding site)
Plmasin is not generated and fibrin is not degraded into its split products

Use:
Control of bleeding caused by different conditions (ie. GI bleeding, dental procedure bleeding)
CRASH-2 study showed that administration within 8 hours of injury in adult trauma patients reduced all-cause
mortality (benefit may be better within 3 hours)

Side Effects:
Thrombosis

Contraindications:
In patients with intracranial bleed/cerebral hematoma expansion (associated with ischemic stroke and
hydrocephalus due to reduced clearance of intraventricular blood)
In patients with DIC (may cause paradoxical thrombosis)
Antiplatelets:

Basic Facts:
Not all conditions presenting with thrombocytopenia lead to bleeding (ie. HIT an TTP)
Antiplatelets do not cause thrombocytopenia per se (with the exception of drug induced TTP)
o Rather, they cause a QUALITATIVE defect in platelets

Monitoring of Antiplatelet Drugs:
Important Point: these tests are not widely available in practice
Two Tests:
o Bleeding Time: two incisions made and time for clotting recorded (normal is 1-9 minutes)
o Optical Aggregometry: light transmission aggregation (measure residual platelet activity)

Normal value varies, but >50% aggregation is typically considered unacceptable residual
platelet activity

Aspirin:
MOA: IRREVERSIBLE inhibition of COX-1/COX-2 (leads to decreased TXA2 and decreased platelet aggregation)
Dosing: 75-325mg/day
o Maintenance doses >325mg are rarely used these days
o Doses of 75-325mg/day are equal in efficacy to 500-1500mg/day for the prevention of MI and stroke
Side Effects:
o Bleeding: anywhere

Hold >5 days before an invasive procedure (platelet half-life is 7-10 days, and this time is
needed for regeneration of new platelets; due to IRREVERSIBLE inhibition)
o Dyspepsia and GI bleeding: esp. in elderly and patients with history of ulcers

Consider gastric protection (ie. with PPIs) in patients using NSAIDs with above risk factors
o Tinnitus: only in over exposure

ADP Inhibitors:
Dipyridamole:
o MOA: interferes with adenosine uptake (reduces platelet adhesion and aggregation)
o Use: rarely used; considered a subpar antiplatelet by most clinicians

Always used in combination with aspirin (monotherapy has poor efficacy)

Sometimes used in the treatment of stroke
o Side Effects: due to vasodilatory action

Vertigo

Headache

Flushing
o Contraindications: use with caution in patients with severe CAD
o DDIs: affects on adenosine may cause it to interact with the following

Theophylline

Caffeine

Commercial adenosine (used for stress test and treatment of SVT)
o Pharmacokinetics:

Poor absorption

Short half life (therefore, should only use XR formulation- not immediate release)
P2Y12 Receptor Antagonist:
o Clopidogrel:

MOA: prodrug that causes IRREVERSIBLE blockage of the P2Y12 receptor (blocks ADP actionblocks platelet activation and aggregation)

Indications:
 ACS: US, NSTEMI, STEMI, recent MI
 Stents: bare metal and drug-eluting stents
 Cerebrovascular Disease: recent stroke
 Peripheral Vascular Disease
 ASA Allergy/Intolerance

Dosing: once a day (okay to use with ASA)

o
o
Side Effects:
 Bleeding: esp. if combined with ASA in stroke patients
o Hold >5 days before invasive procedure
 TTP: microthrombotic process at endothelial level (rare)
 GI Distress: bleeding (esp. if history of NSAID-induced ulcers)
o Patients with GI bleed while on ASA/NSAIDs were not better off upon
rechallenge with clopidogrel
o Better to rechallenge with lower dose of ASA + PPI

Problems with Clopidogrel:
 30% Non-Responders:
o Erratic and incomplete absorption (may be pH dependent)
o Presence of CYP2C19 loss-of-function allele (prodrug isn’t activated)
 High Risk of Bleeding:
o In patients with extensive CYP2C19 metabolism (excessive activation of
prodrug)
Prasugrel:

MOA: prodrug that causes IRREVERSIBLE blockage of the P2Y12 receptor (blocks ADP actionblocks platelet activation and aggregation)

Dosing: once a day (okay to use with ASA

Use: ACS

Side Effects:
 Excessive bleeding in some patients: due to more potent effects
o Those who have had ischemic stroke/TIAs
o Elderly (>75)
o Underweight (<60kg)
 Because of bleeding risk:
o Hold >5 days before surgery

Reserved for:
 Younger patients
 Patients with good kidney function
 Patients with NO history of stroke
 Patients who are NOT underweight

Advantages Over Clopidogrel:
 One-step activation instead of 2 like clopidogrel (not subject to as many
interactions or CYP2C19 genetic polymorphisms)
o More efficient general of active metabolite
o Quicker anti-platelet response
o More potent/prolonged anti-platelet effect
Ticagrelor:

MOA: REVERSIBLE blockage of the P2Y12 receptor (blocks ADP action- blocks platelet
activation and aggregation)
 Both drug itself and its metabolite are active
 Because of reversible block, supposed to wear off quickly (but did not pan out)
 Offset before surgery is still ~5 days

Indications:
 ACS: reduces rate of thrombotic CV events (US/NSTEMI/STEMI)
o Reduces rate of stent thrombosis in patients with PCI

Dosing: TWICE a day dosing (can only use with ASA doses of ≤100mg/day)

Side Effects:
 Dyspnea (goes away with continuous treatment; unknown mechanism)
Iron Supplements:

Use: treatment of anemia (ie. chronic renal failure, menstrual bleeding)

Different Formulations:
Oral Formulations: patients need to be treated for at least 3-6 mos (parameters improve in 3-4 wks)
o Ferrous gluconate (12%)
o Ferrous sulfate (20%); ferrous sulfate anhydrous (30%)
o Ferrous fumarate (33%)

o Polysaccaride iron complex (100%)
o Heme iron polypeptide (100%)
IV Formulations: superior to oral for hemodialysis patients with anemia of chronic disease
o Low molecular iron dextran
o Iron gluconate
o Iron sucrose
Side Effects:
GI Effects: mostly constipation
o Less iron content= less constipation
o Slow release iron preparations said to have less side effects, but are also less effective because of poor
absorption
Iron Chelators:

Agents:
Deferoxamin (IV)
Deferasirox (oral; developed due to lack of compliance with infusion therapy )

Use: patients with iron overload conditions (genetic or acquired)
Most acquired causes due to blood transfusions
Parenteral deferoxamine shown to reduce incidence of iron-induced complications and mortality

Goal of Therapy: serum ferritin consistently below 500ug/L
Takes ~3-6 months of treatment to reach these levels

Side Effects:
o GI effects
o Liver failure
o Renal failure
o Agranulocystosis
o Risk of infections
Vitamin B12:

Function: necessary for transfer of methylTHF from plasma to RBCs
Deficiency leads to decrease in RBC nucleic acids, and delayed maturation of nucleus compare to cytoplasm
Results in macrocytic anemia with hypersegmented PMNs on smear

Treatment of Megaloblastic Anemia: response to therapy can be seen as early as 2 weeks (full response by 8 weeks)
Time to Response: slower than with folic acid deficiency
Neurological Symptoms: requires the use of PARENTERAL vitamin B12 as starting treatment
o Given subQ or IM
o Required to give supra-therapeutic doses in order to resolve neurological impairment

Formulations:
Hydroxycobalamin (preferred in Europe, stays in body for 6-12 months after 1 dose)
Cyanocobalamin (preferred in US, stays in body for 2 weeks after 1 dose)
MALIGNANT HEMATOLOGY:
Tyrosine Kinase Inhibitors:

Imatinib:
Use: inhibits the proliferation of the bcr-able fusion protein by binding to ATP binding pocket of TKs
o Bcr-abl encoded by Ph cs/t(9;22); characteristic of CML
o Bcr-abl normally causes unregulated activity of tyroskin kinase (abl)
o Has a 70% complete cytogenetic remission rate in chronic phase of CML (but not a CURE)

Not active against CML with T315I mutation (gatekeeper mutation)
Side Effects:
o Myelosuppression
o Edema (mostly PERIPHERAL)**
o Liver function abnormalities
o QT interval prolongation
o Rash
o GI irritation
o Muscle cramps
o Arthralgias

Dasatinib:
Use: imatinib-refractory CML patients (can circumvent bcr-abl resistance)
o Also not a cure (similar to imatinib) but likely to provide longer remission
o Not active against CML with T315I mutation (gatekeeper mutation)
o 325x more potent than imatinib
o Can also be used to treat more kinase-dependent tumors (ie. GIST, renal cell carcinoma)

Inhibits both ABL and Src kinases (imatinib and nilotinib only inhibit ABL kinase)
Overcoming Imatinib Resistance:
o Inhibits Src kinase
o Binds to ABL kinase in both active and inactive conformations
Side Effects:
o Myelosuppression
o Edema (mostly PLEURAL/PERICARDIAL)**
o QT prolongation

Nilotinib:
Use: imatinib-refractory CML patients (can circumvent bcr-abl resistance)
o Also not a cure (similar to imatinib) but likely to provide longer remission
o Not active against CML with T315I mutation (gatekeeper mutation)
o 30x more potent than imatinib
Side Effects:
o Myelosuppression
o Liver function abnormalities
o QT prolongation (may be more pronounced and even cause sudden death)
Hypomethylating Agents:

Agents:
Azacitidine: first ever drug to show survival benefit in MDS
Decitabine: use has not yet translated into survival

MOA: inhibit DNA methyltransferase, leading to hypomethylation of DNA (need to be incorporated into DNA first)
End result is cell apoptosis and reversal of epigenetic silencing that leads to premalignant/potentally neoplastic
phenotype

MOA at Higher Doses (20x): DNA methyltransferase inhibition results in cytotoxic effects instead of hypomethylation
Cytotoxic effects are NOT the intent of the current use of this class

Onset of Clinical Response: takes several doses and cycles due to MOA
Agent needs to be incorporated into DNA to inhibit methyltransferase
Takes two cycles of DNA replication before the DNA may be entirely demethylated (hemimethylated first)
May take more because some remethylation may occur at the same time

Toxiucity:
Myelosuppression
GI toxicity
Anti-CD20 Antibodies:

Rituximab:
MOA: binds to CD20 and causes activation of the complement cascade
o Generates MAC  lyse B cells (complement-mediated cytotoxicity)
o Coats with C3b phagocytosis (antibody-dependent cell-mediated cytotoxicity or ADCC)
o Interaction with NK cells and Fc portion of rituximab  ADCC
Treatment: revolutionized the treatment of low and intermediate grade lymphoma
o Used to be treated with CVP (cycophosphamide, vincristine, prednisone)
Risks: activation of ADCC can lead to a cytokine release (infusion related reaction) that can be fatal
o Risk diminishes with subsequent treatment cycles (virtually absent after 4 cycles)