HD1 – Pharmacology Lipid Lowering Agents I) Review of Cholesterol Metabolism A) Endogenous pathway 1) Liver uses HMG-CoA reductase to synthesize cholesterol as part of the mevalonate pathway B) Exogenous pathway 1) Recycling of bile salts C) Dietary uptake 1) Dietary fatty acids are absorbed in the gut and packaged into chylomicrons 2) Lipoprotein lipase produces triglycerides from chylomicrons and VLDL II) Evaluating Risk A) Lowering LDL and raising HDL lower risk 1) The lower the LDL, the better B) Therapeutic lifestyle changes (SCOPE) 1) Saturated fat reduction to <7% total calories 2) Cholesterol intake limited to 200 mg/day 3) Obesity treatment 4) Plant sterols (2 g/day) 5) Exercise III) Statins A) Mechanism 1
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HD1 – Pharmacology
Lipid Lowering Agents
I) Review of Cholesterol MetabolismA) Endogenous pathway
1) Liver uses HMG-CoA reductase to synthesize cholesterol as part of the mevalonate pathwayB) Exogenous pathway
1) Recycling of bile saltsC) Dietary uptake
1) Dietary fatty acids are absorbed in the gut and packaged into chylomicrons2) Lipoprotein lipase produces triglycerides from chylomicrons and VLDL
II) Evaluating RiskA) Lowering LDL and raising HDL lower risk
1) The lower the LDL, the betterB) Therapeutic lifestyle changes (SCOPE)
1) Saturated fat reduction to <7% total calories2) Cholesterol intake limited to 200 mg/day3) Obesity treatment4) Plant sterols (2 g/day)5) Exercise
III) StatinsA) Mechanism
1) Reversible inhibition of HMG-CoA reductase, hindering endogenous cholesterol production in the liver
2) By reducing endogenous cholesterol production, the liver withdraws more LDLs from circulation, harvesting their cholesterol for synthetic purposes
B) Pharmacokinetics1) Oral tablet before bedtime, as HMG-CoA reductase is more active at night
(a) Half-life of 1-2 hours2) Hepatic metabolism (CYP450, CYP3A4)
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(a) Other drugs that utilize/interfere with the same pathways may precipitate toxicities3) Excretion in bile, feces, and urine
C) Side effects1) Myopathy (rhabdomyolysis in exceedingly rare cases)2) Liver disease (elevated ALT and AST)3) Cognitive effects4) Hyperglycemia5) Contraindicated in pregnancy (teratogen)6) GI cramps, abdominal pain, and constipation
D) Specific drugs1) Lovastatin2) Pravastatin3) Simvastatin4) Fluvastatin5) Atorvastatin (Lipitor)6) Rosuvastatin (Crestor)7) In general, the newer, synthetic statins are more effective
IV)FibratesA) Mechanism
1) PPARα agonist that promotes transcription of lipoprotein lipase (LPL), which degrades chylomicrons and VLDL
2) Thus, free triglycerides are lowered and HDL is increasedB) Pharmacokinetics
1) Oral dosing2) Excreted in urine
C) Side effects1) GI disturbance2) Skin rashes3) Contraindicated in hepatic, renal, and gall bladder disease
D) Specific drugs1) Gemfibrozil2) Fenofibrate
V) Bile Acid Resins (BARs)A) Mechanism
1) Chelate bile salts in the gut, promoting their elimination2) Because fewer bile salts are being recycled, the liver must synthesize new ones, consuming
cholesterol in the process3) Can be used in conjunction with statins for a cumulative effect
(a) Or, in patients adverse to statins, BARs can be used with a greatly reduced statin load to produce an equivalent effect
B) Side effects1) As these are not systemic drugs, there is little toxicity2) Contraindicated in patients with hypertriglyceridemia
C) Specific drugs1) Cholestyramine (old, no longer used)2) Colestipol (old, no longer used)3) Coleselevam (newer, only one used)
VI)HDL RaisersA) Mechanism
1) Decreases lipolysis in adipose tissue2) Produces a favorable outcome in all lipids
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B) Side effects1) Numerous, limiting use2) Contraindicated in diabetics, as it may produce hyperglycemia
C) Specific drugs1) Niacin (nicotinic acid, vitamin B3)
VII) New TherapiesA) Ezetimibe
1) Inhibits cholesterol absorption in the gut by specifically blocking intestinal cholesterol transportB) CETP inhibitors
1) Inhibition of cholesteryl ester transfer protein (CETP), which converts HDL to LDL, yields a more favorable HDL:LDL ratio
C) PCSK9 inhibitors1) PCSK9 reduces the number of LDL receptors, so inhibiting it would increase LDLR and promote the
withdrawal of LDL from plasma
Comparison of AntihyperlipidemicsDrug LDL HDL TG Side EffectsStatins Myalgia, myositis, rhabdomyolysisFibrate
s Toxic when used with statins
Niacin HyperglycemiaBARs Increased triglycerides
Anti-Anginal Drugs
I) AnginaA) Definition
1) Predictable occurrence of substernal pain due to transient myocardial ischemiaB) Three types of clinically recognized angina
1) Stable angina(a) Occurs with exertion(b) Predictable pain(c) Frequently due to coronary atheromas(d) 90% of cases and focus of anti-anginal drug development
2) Unstable angina(a) Platelet/fibrin thrombus with ruptured plaque
3) Variant angina(a) Coronary artery vasospasm
C) Therapeutic strategies1) Decrease myocardial oxygen demand
B) Specific drugs1) Glyceryl trinitrate2) Isosorbide dinitrate3) Isosorbide mononitrate
C) Pharmacokinetics and dosing1) Glyceryl trinitrate
(a) 100% first-pass metabolism fast onset (30 sec) and short half life (3 min)(b) Low oral bioavailability (<1%)(c) Administered as a sublingual tablet
2) Isosorbide dinitrate(a) Moderate oral bioavailability (~20%)(b) Administered as a sublingual tablet
3) Isosorbide mononitrate(a) No first-pass metabolism slow release preparations with long half life(b) High oral bioavailability (100%)(c) Oral, topical, and transdermal administration
(i) Susceptible to rapid tolerance developmentD) Nitrate tolerance
1) Tolerance can develop rapidly when sustained release formulations are used2) Tolerance can be minimized by several methodologies
(a) Limit amount of long-lasting nitrates(b) Incorporate a “nitrate free period” (~8 hours) between sustained release dosing(c) Combination therapy that reduces nitrate use
E) Adverse effects1) Dose-related extensions of vasodilation
(a) Pulsating headache(b) Postural hypotension(c) Dizziness and syncope(d) Reflex tachycardia
2) Contraindicated in patients with elevated intracranial pressureIV)Calcium Channel Blockers
A) Mechanism
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1) Inhibition of calcium channels in the plasma membrane of cardiomyocytes decreased intracellular [Ca2+] decreased contractility decreased O2 demand
2) Inhibition of calcium channels in the plasma membrane of vascular smooth muscle cells decreased intracellular [Ca2+] vasodilation decreased cardiac preload decreased O2 demand
B) Specific drugs1) Verapamil (cardiac mechanism)2) Nifedipine (vascular mechanism)
(a) Preferred in patients with heart failure(b) Used in sustained release formulations
3) Diltiazem (cardiac and vascular mechanisms)C) Pharmacokinetics and dosing
1) Oral administration2) High first-pass liver metabolism
D) Side effects1) Contraindicated in patients taking β-blockers, as a drastic decrease in cardiac contractility may occur2) Headache, nausea, and flushing
V) New TherapiesA) Ranolazine
1) Indicated for patients who continue to be symptomatic while taking β-blockers, nitrates, or calcium channel blockers
2) Reduces calcium overload in the ischemic cardiomyocyteB) Ivabradine
1) Indicated for patients with chronic angina who continue to be symptomatic while taking β-blockers, nitrates, or calcium channel blockers
2) Blocks cardiac current decreased heart rateVI)Therapeutic Prevention of MI
1) Agonism of β2 receptors in the respiratory tract bronchodilation5
B) Delivered via inhalation, providing the most rapid onset of action1) Short-acting drugs are typically used for quick relief in emergent situations2) Long-acting drugs are typically used as part of a combination therapy for managing moderate/severe
D) Specific drugs1) Albuterol (short-lasting)2) Terbutaline (short-lasting)3) Salmeterol (long-lasting)
III) Anti-Leukotriene AgentsA) Mechanism
1) Leukotrienes are eicosanoid mediators of inflammation that trigger contraction of bronchiolar smooth muscle cells
2) CysLT-R1 antagonists block the leukotriene receptor, preventing bronchoconstriction3) Leukotriene synthesis inhibitors block the synthesis of LTs, preventing bronchoconstriction
B) Delivered orally1) Not useful for immediate relief2) Can be used in conjunction with β2-agonists for an additive effect (or dose reduction of the latter)3) Typically used for early management of mild asthma
1) Antagonism of muscarinic receptors in bronchial smooth muscle bronchodilation2) Antagonism of muscarinic receptors in parasympathetic ganglia bronchodilation
B) Delivered via inhalation1) Used as second-line drugs when other methods fail to control asthma
C) Side effects1) Dry mouth2) Glaucoma3) Urinary retention
D) Specific drugs1) Ipratroprium2) Tiotropium
V) XanthinesA) Mechanism
1) May act as phosphodiesterase inhibitors bronchodilation2) May act as adenosine blockers bronchodilation
B) Delivered orally1) Used as second-line drugs when other methods fail to control asthma
C) Side effects1) Arrhythmia2) Nausea and vomiting
D) Specific drugs6
1) TheophyllineVI)Glucocorticoids
A) Mechanism1) Transcriptional down-regulation of pro-inflammatory mediators (PLA2, TH2, cytokines, PGI2, PGE2)
B) Dosing and indications1) Inhaled corticosteroids (ICS) are used as the first-line therapy for all levels of persistent asthma2) Systemic (oral) corticosteroids are used for treatment of severe and emergency asthma3) Combination therapy with long-acting β2-agonists may help control severe persistent asthma
C) Side effects1) Hepatotoxicity, especially when inhaled improperly
1) Inhalation drug only useful prophylactically2) Especially effective in children
C) Very few side effectsD) Specific drugs
1) Cromolyn2) Nedocromil
VIII) Anti-IgE Antibody TherapyA) Mechanism
1) Humanized IgG monoclonal antibodies bind IgE and hinder mast cell degranulationB) Intravenous therapy only used in the most severe persistent asthma
1) Hinderingly expensiveC) Specific drugs
1) OmalizumabIX)Phosphodiesterase-4 Inhibitors
A) Mechanism1) Inhibition of PDE4 may treat the chronic inflammation underlying COPD
B) Oral administration1) Used in conjunction with bronchodilators
C) Side effects1) Nausea2) Diarrhea3) Headache
D) Specific drugs1) Roflumilast
Drugs for Congestive Heart Failure
I) IntroductionA) Compensatory mechanisms to heart failure
1) When cardiac output begins to fall, both sympathetic discharge and renin release increase2) Increased renin increased angiotensin II several effects
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(a) Increased aldosterone increased fluid retention increased preload(b) Vasoconstriction increased afterload(c) Increased sympathetic discharge progression of the cycle
3) Ultimately, ventricular remodeling occurs, which is greatly detrimental
B) Treatment objectives1) Improve survival (obviously)2) Improve cardiac function while reducing symptoms3) Attenuate the neurohormonal changes4) Attenuate progression of CHF
1) Inhibition of ACE decreased [angiotensin II] several effects(a) Vasodilation decreased peripheral resistance decreased afterload increased cardiac
output(b) Venodilation (minor) decreased left ventricular end diastolic pressure (LVEDP)(c) Decreased myocardial oxygen demand(d) Diuresis and natriuresis decreased blood volume decreased blood pressure
B) Advantages of ACE inhibitors1) Inhibit left ventricular remodeling2) Increase survival while decreasing hospitalizations3) No neurohormonal activation (e.g., reflex tachycardia)4) Tolerance does not develop
C) Side effects1) Cough
(a) ACE also degrades bradykinin, which induces coughs (mechanism unknown)(b) Thus, ACE inhibitors increase [bradykinin] bronchoconstriction dry cough(c) Presence of this cough is a key indicator that ACE inhibitors should be discontinued and ARB
1) Competitive antagonism of the AT1 receptor several effects(a) Vasodilation decreased peripheral resistance decreased afterload increased cardiac
output(b) Venodilation (minor) decreased left ventricular end diastolic pressure (LVEDP)(c) Decreased myocardial oxygen demand(d) Diuresis and natriuresis decreased blood volume decreased blood pressure
B) Advantages of ARBs1) Patients who cannot tolerate ACE inhibitors can typically use ARBs2) May allow the favorable interaction of angiotensin II and the AT2 receptor (entirely theoretical)
C) Side effects1) Proteinuria2) Hypotension3) Hyperkalemia
(a) May be beneficial in cardiac hypertrophy, as it may hinder ventricular remodeling(b) Useful in pulmonary arterial hypertension
4) Side effects(a) Headache(b) Flushing(c) Epistaxis(d) Vision changes
5) Contraindications(a) Co-administration with nitrates
C) Hydralazine1) NO preservative delivered orally in conjunction with a nitrate2) Mechanism
(a) Unknown, but somehow stabilizes NO and prolongs its effect3) Side effects
(a) Lupus-like syndrome4) Contraindications
(a) Do not deliver this drug alone, as it will cause a profound reflex tachycardia(i) Must be co-administered with a nitrate, such as isosorbide dinitrate (ISDN, above)
output(b) Venodilation (minor) decreased left ventricular end diastolic pressure (LVEDP)(c) Decreased myocardial oxygen demand(d) Diuresis and natriuresis decreased blood volume decreased blood pressure
B) Side effects1) Non-selective drugs induce β2-blockade vasoconstriction, bronchospasm, Raynaud’s phenomenon2) Heart failure3) Bradycardia4) AV block5) Fatigue, depression, and impotence are rare
C) Specific drugs1) Bisoprolol2) Carvedilol (both α- and β-antagonism)3) Nebivolol (may activate eNOS, furthering vasodilation)
(i) Arrhythmia, SA block, and AV block(ii) Nausea, vomiting, diarrhea(iii) Depression, disorientation, paresthesia(iv)Blurred vision, scotomas(v) Hyperestrogenism, gynecomastia, galactorrhea
3) Specific drugs(a) Digoxin
(i) While digoxin increases functional status in patients, it does not decrease mortalityB) Sympathomimetics (β-adrenergic receptor agonists)
1) Specific drugs(a) Dopamine
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(b) DobutamineC) Phosphodiesterase inhibitors
1) Specific drugs(a) Inamrinone
(i) PDE3 inhibitor that increases [Ca2+] in the heart
Antimicrobials I & II
I) β-LactamsA) Mechanism of action
1) Inhibits transpeptidase inhibition of cell wall assembly2) Bactericidal, but less effective against non-dividing cultures as they are not synthesizing new cell
wall material as frequentlyB) Pharmacokinetics
1) Oral absorption, but bioavailability varies with the specific type2) Most are excreted in urine3) Widely distributed throughout the body except for the CNS
C) Resistance mechanisms1) Many bacteria have evolved penicillinase, an enzyme that degrades the β-lactam ring and renders the
antibiotic useless2) Altered penicillin binding proteins, hindering drug uptake
(a) For example, MRSA is resistant because of its low-affinity binding proteinsD) Adverse reactions
1) Allergy anaphylactic shock2) Toxicity is relatively low with a high therapeutic index3) GI disturbance is seen (as it is with many oral antibiotics that have the potential to disrupt the normal
gut flora)E) Specific drugs
1) Penicillin G(a) Effective against G+ and G- cocci(b) Oral bioavailability is low, so IV or IM administration is preferred
2) Penicillin V(a) Similar to penicillin G(b) Oral bioavailability is improved sufficiently for oral administration
3) Oxacillin(a) Replaced methicillin(b) Resistant to penicillinase, making it useful for Staphyococci and Streptococci that may produce
the enzyme4) Ampicillin
(a) Effective against G+ and G- bacilli(b) Not a substitute for penicillin G or V(c) Resistance is increasing
5) Piperacillin(a) Extended spectrum penicillin that is typically reserved for serious G+ and G- infections
6) Clavulanic acid(a) Inhibitor of penicillinase that is administered alongside β-lactams to increase their efficacy(b) Has no antimicrobial properties when used alone(c) Amoxicillin + clavulanic acid = augmentin
II) CephalosporinsA) Mechanism
1) These are β–lactam-containing structures that act similar to penicillin12
B) Pharmacokinetics1) Absorption and distribution varies with type2) Largely excreted in urine
C) Resistance mechanisms are similar to penicillin1) Cephalosporinase2) Penicillinase3) Low-affinity penicillin binding proteins
(a) Cephalosporins are not reliably effective against MRSA(i) One exception is a recently developed fifth-generation cephalosporin that has been approved
for MRSA treatment in certain scenariosD) Adverse reactions (generally well tolerated)
1) GI disturbance2) Allergy3) Nephrotoxicity (may be allergic response)4) Superinfection due to G- inhibition
E) Generations1) There are four (now five) generations of cephalosporins2) As one progresses through the generations, the following characteristics change
3) For example, a first-generation cephalosporin would be expected to be effective against G+ bacteria, ineffective against many G- bacteria, and be excluded from the CNS
4) A fourth-generation cephalosporin, however, would be expected to be effective against an expanded range of G- bacteria, have poor G+ efficacy, and readily penetrate the CNS
III) Carbapenems (Imipinem)A) Mechanism
1) These are also β-lactam-containing antibiotics that function in a similar manner to penicillin2) Relatively broad spectrum of action, including G- rods, G+ organisms, and anaerobes
B) Pharmacokinetics1) Parenteral administration (i.e., not oral)2) Renal metabolism
(a) In fact, they are metabolized so readily by the kidney that all carbapenems are co-administered with the renal dehydropeptidase inhibitor cilastatin (which is pre-formulated into the drug)
3) Excreted in urine4) Penetrates CNS
C) Resistance mechanisms similar to penicillin1) However, these are generally resistant to β-lactamase2) Still not useful for MRSA or VRE
D) Adverse reactions1) Neurotoxicity (e.g., seizures)2) GI disturbance3) Superinfection4) Allergy
IV)VancomycinA) Mechanism
1) Inhibits transport of cell wall precursors across cell membrane2) Bactericidal (only bacteristatic in Enterococci)3) Only effective against G+ organisms
B) Pharmacokinetics1) IV administration
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(a) Oral administration is used to treat gut infections, but the poor bioavailability makes oral delivery inappropriate for systemic infections
2) Renal metabolism and excretionC) Resistance mechanisms
1) Few, but VRE, MRSA, VISA, and VRSA strains are on the riseD) Adverse effects
1) Allergy2) Ototoxicity (hearing loss) and nephrotoxicity associated with high doses
V) DaptomycinA) Mechanism
1) Destabilizes the cell membrane in bactericidal fashion2) Effective against G+ organisms
B) Pharmacokinetics1) IV administration2) Renal elimination
C) Resistance mechanisms1) Rarely observed and poorly understood2) Can be used to treat MRSA bacteremia
D) Adverse effects1) Muscle pain/weakness
VI)Aminoglycosides (Tobramycin)A) Mechanism
1) Blocks the initiation of protein synthesis2) Rapidly bactericidal3) Effective against aerobic G- organisms
(a) Ineffective against anaerobesB) Pharmacokinetics
1) IM or slow IV administration2) Oral administration to treat gut infections only, as oral bioavailability is poor3) Topical applications in burn patients4) Renal excretion
C) Resistance mechanisms1) Trans-membrane uptake requires oxygen, rendering anaerobes (and facultative anaerobes) resistant2) Plasmid-encoded enzymes grant resistance3) Ribosomal mutants may be resistant to one aminoglycoside
D) Adverse reactions1) Ototoxicity and nephrotoxicity2) Crosses the placenta, potentiating fetal damage
VII) Tetracyclines (Doxycycline)A) Mechanism
1) Inhibition of the 30S ribosomal subunit prohibits protein synthesis2) Bacteriostatic3) Drug of choice for Rocky Mountain spotted fever, Q fever, Chlamydiae infection, and Mycoplasma
pneumoniaeB) Pharmacokinetics
1) Good oral bioavailability(a) Co-ingestion of dairy products reduces the uptake of some tetracyclines, but not doxycycline
2) Wide distribution, including CNS and placental diffusion3) Renal metabolism and excretion
C) Adverse reactions1) GI disturbance
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2) Pseudomembranous enterocolitis3) Tooth discoloration in fetus (avoid in pregnancy)4) Superinfection (Candida albicans)
VIII) Macrolides (Erythromycin)A) Mechanism
1) Inhibits translocation of the 50S ribosomal subunit, prohibiting protein synthesis2) Bacteriostatic (though clinical doses can be bacteriocidal)3) Useful against G-, G+ aerobic, and some anaerobic organisms
(a) Not effective against MRSA B) Pharmacokinetics
1) Oral or IV administration2) Does not penetrate CNS3) Hepatic metabolism
(a) May precipitate CYP450 drug interactionsC) Resistance mechanisms
1) Roughly 50% of hospital cases of Staphylococci are resistant to erythromycin2) Not effective against MRSA
D) Adverse reactions1) GI disturbance2) Side effects are rare, and erythromycin is perhaps one of the safest antibiotics in use3) Used for serious G+ infections in penicillin-allergic patients
IX)ClindamycinA) Mechanism
1) Protein synthesis inhibitor2) Bacteriostatic (may be bacteriocidal in some organisms)
B) Pharmacokinetics1) Oral, IM, IV, and topical administration2) Does not distribute to CNS3) Hepatic metabolism
C) Resistance mechanisms1) Roughly 50% of hospital cases of Staphylococci are resistant to erythromycin2) Not effective against MRSA
D) Adverse effects1) GI disturbance2) Pseudomembranous enterocolitis
X) LinezolidA) Mechanism
1) Protein synthesis inhibitor2) Effective against VRE, MRSA, etc.
B) Pharmacokinetics1) Oral administration2) Hepatic metabolism3) Renal excretion
C) Adverse effects1) GI disturbance2) Headache
XI)Sulfonamides (Sulfamethoxazole)A) Mechanism
1) PABA analog that inhibits folate synthesis(a) Often used in conjunction with trimethoprim, which inhibits folate synthesis at a different step
2) Bacteriostatic15
B) Pharmacokinetics1) Oral administration2) Distributes to CNS3) Liver metabolism4) Renal excretion
C) Resistance mechanisms1) Multiple
D) Adverse reactions1) Crystallization in bladder2) Acute hemolytic anemia3) Aplastic anemia4) Bone marrow suppression5) Allergy
XII) TrimethoprimA) Mechanism
1) DHFR inhibitor that hinders folate synthesis(a) Often used in conjunction with sulfamethoxazole, which inhibits folate synthesis at a different
1) Mechanism(a) Irreversible acetylation of COX decreased TXA2 (platelet effect) and decreased PGI2
(endothelial effect) decreased platelet activation(b) Endothelium can resynthesize COX, but platelets must be turned over (10-15% per day)
2) Adverse reactions(a) Generalized bleeding(b) GI toxicity(c) Resistance (controversial)
B) Clopidogrel1) Mechanism
(a) Irreversible antagonism of ADP receptor decreased platelet activation2) Pharmacokinetics
(a) Oral pro-drug(b) Liver metabolism to active form(c) Maximal platelet inhibition takes 4-7 days(d) Additive effect when used in conjunction with aspirin
(a) Reversible antagonism of ADP receptor decreased platelet activation2) Pharmacokinetics
(a) Oral dosing(b) Not a pro-drug(c) Faster acting, but shorter duration of effect when compared to clopidogrel(d) Additive effect when used in conjunction with aspirin
D) Abciximab20
1) Mechanism(a) Inhibition of glycoprotein IIb/IIIa prevention of fibrinogen binding potent inhibition of
platelet aggregation(b) One of the most potent platelet inhibitors developed
2) Pharmacokinetics(a) IV administration(b) Used as an adjunct to heparin/aspirin in post-surgical situations
3) Adverse reactions(a) May increase mortality
E) Esoprostenol1) Mechanism
(a) Synthetic PGI2 that inhibits platelet aggregation2) Specialized application
(a) IV infusion in hemodialysis if heparin is contraindicatedF) Cilostazol
1) Mechanism(a) Inhibits platelet PDE-3 increased cAMP activation of PKA inhibition of platelet
aggregation2) Indications
(a) Peripheral artery disease(b) Claudication (pain in legs upon walking)
III) AnticoagulantsA) Heparin
1) Mechanism(a) Binds antithrombin III (ATIII) and enhances proteolytic activity increased degradation of
clotting factors(i) Factors IIa (thrombin) and Xa are most sensitive to degradation by ATIII(ii) Degradation of thrombin is enhanced by electrostatic interactions between it and heparin
2) Pharmacokinetics(a) IV dosing(b) Fast acting(c) Polymer of various size(d) Therapeutic range is non-linear and needs to be individualized to each patient(e) Binds proteins unpredictably(f) May be cleaved by macrophages