Flashcards 3

Alteplase Abciximab (Activase (ReoPro)

)

Anistreplase Amino Caproic Acid (Eminase (Amicar)

Aprotinin (FDA has suspended marketing)

)

Ardeparin

(Trasylol )

Aspirin Argatroban (Acetylsalicylic (Acova)

acid)

Clopidogrel Bivalirudin (Plavix (Angiomax)

)

Fibrinolytic (Thrombolytic) tPA (tissue plasminogen activator) that is produced by recombinant DNA technology & has ½ life of 4-8 min Requires fibrin for activity so may only activate plasminogen in situ so it should cause less random proteolytic destruction of blood clotting factors (lytic state), which occurs when plasminogen is activated in the blood; May have ability to lyse more highly cross-linked fibrin, which is a consideration for pts who have had symptoms of longer duration; Approved in acute ischemic stroke (w/in 3hrs onset & after exclusion of intracranial hemorrhage)

Antiplatelet Agent – GPIIb/IIIa Antagonist Fab fragment of a monoclonal antibody that prevents platelet aggregation by binding to the platelet glycoprotein IIb/IIIa receptor, which prevents binding of adhesive glycoproteins (fibrinogen, von Willebrand factor, etc) to surface of activated platelets (This is the Final Common Pathway of Platelet Aggregation); Not Specific for GPIIb/IIIa; Rapid onset; Activity lasts for 24-48hrs; Elimination by platelet binding; Hospital use only; Antibody response possible Adverse effects: bleeding (usu at site of arterial access), thrombocytopenia (more than other GPIIb/IIIa antagonists)

Hemostatic Fibrinolytic (Thrombolytic) - Anisoylated Plasminogen Streptokinase Activator complex (known as APSAC) Binds reversibly to plasminogen and thereby blocks the An acylated inactive complex of streptokinase and human lysbinding of plasminogen to fibrin & its activation and plasminogen with a ½ Life of 70-120 minutes transformation to plasmin Upon injection, the acyl group is hydrolyzed slowly to produce an activator that converts plasminogen to plasmin Useful in enhancing hemostatic when fibrinolysis contributes Can cause proteolytic destruction of blood clotting factors to bleeding, but not FDA approved for bleeding (lytic state), which occurs when plasminogen is activated in accompanying fibrinolytic use the blood stream b/c it does not require fibrin for activity Contraindicated in patients with DIC

Low Molecular Weight Heparin Not on market

Broad spectrum polypeptide serine protease inhibitor, isolated from bovine lung; forms complex w/ plasmin, kallikreins, & other factors to block kinin & fibrinolytic systems; Admin iv to modulate systemic inflam response (SIR) & risk of stroke assoc w/ high risk coronary artery bypass grafting (CABG); Attenuates inflam resp, fibrinolysis, & thrombin generation; preserves platelet function bleeding & need for transfusions; can be given w/ heparin to prevent thrombosis; Allergic/anaphylactoid rxn may occur, assoc. w/ serious organ damage (2-3X risk of renal failure req dialysis, risk of MI or heart failure & risk of stroke or encephalopathy

Salicylate -Analgesic, antipyretic & anti-inflammatory Uses: Juvenile RA, MI & colon cancer prevention Direct reversible thrombin inhibitor, including clot-bound CI: asthma, gout, ulcer, influenza thrombin Inhibits PG biosynthesis (irreversible acetylation of COX); Synthetic blocks platelet aggregation for life of platelets (8-10d); Oral Admin iv (infusion); ½ life is short (40-50min) well absorbed ½ t 15-30 min., Mainly excreted as salicyluric Hepatic eliminated so not affected by renal impairment acid by kidney; NSAIDS prior to ASA may protect COX so (unlike lepirudin) take ASA 2h before NSAID (acetaminophen doesn’t do this) Not immunogenic Monitored by aPTT (1.-3.0 times baseline) Side effects: Tinnitus/deafness (early tox), GI intol., trans. No known antidote renal fxn., hepatotoxicity, respiratory alkalosis-metabolic acidosis, headache, confusion, drowsiness & sweating Oral Prodrug Antiplatelet Agent – ADP Pathway Inhibitor Direct Reversible Thrombin Inhibitor Irreversibly blocks purinergic receptor (P2Y12 coupled to inhib Synthetic 20-amino acid derivative of hirudin (anti-coag in G proteins) for ADP indirectly inhibits binding of leeches) that can inactivate platelet bound Xa & clot bound fibrinogen to platelet receptor GPIIb/IIIa; Better bioavail w/ thrombin (unlike heparin); ½ life in nl renal fxn pts is 25 min; food); metabolized to active form in liver; std dose (75mg/d), dose reductions recommended in pts w/ renal impairment; max inhibition of platelet fxn 3-5 days; loading dose of 300Approved as iv anticoagulant to be used (w/ aspirin, 600mg, accelerates effect to w/in 4-6h; takes ~5d after clopidogrel, & provisional GPI) instead of heparin in pts w/ cessation for plt fxn to return to nl; Adverse effects: diarrhea, unstable angina undergoing PCI; Activity can be monitored by activated clotting time (ACT) or aPTT; Doesn’t cause immune rash (> ASA), abd pain, dyspepsia, GI bleeding (< ASA); thrombocytopenia; major adverse effect is bleeding (< than bleeding in pts. on anti-coag; may cause bone marrow heparin); appears to be at least as effective as high-dose UFH suppression & thrombotic thrombocytopenic purpura

Dalteparin

Dipyridamole

(Fragmin )

(Aggrenox – dipyridamole +aspirin)

Enoxaparin Eptifibatide (Lovenox )

(Integrilin)

Fondaparinux Heparins (Arixtra )

Lepirudin Phytonadione (Vit K1) (Refluda n)

Protamine sulfate

Reteplase

(Retavase)

Low Molecular Weight Heparin w/ Anti-Xa:Anti-IIa ratio of 2.7 (UFH undergone enzymatic or chem depolymerization) Antiplatelet Agent – PDE/Adenosine Uptake Inhibitor MW 5.8kDa; Only ~15-25% has pentasaccharide seq necessary for activity; Excreted primarily by kidneys Adjunct in prevention of prosthetic valve thromboembolism Produces more predictable response than UFH b/c better when used with warfarin bioavail, longer ½ life, & dose-indep cl; used w/out monitoring, for long-term prophylaxis in certain pts Adjunct in prevention of transient ischemia of the brain or Adverse effects: Major bleeding,, HIT (less common than complete ischemic stroke caused by thrombosis in patients UFH); Rx of OD: protamine (neutralizes anti-IIa completely who already had TIA or ischemic stroke. & Xa partially) & Withdrawal of drug NOT INTERCHANGEABLE w/ other LMWHs or UFH Antiplatelet Agent – GPIIb/IIIa Antagonist Low Molecular Weight Heparin w/ Anti-Xa:Anti-IIa ratio Cyclic peptide that prevents platelet aggregation by binding to of 3.8 (UFH undergone enzymatic or chem depolymerization) the platelet glycoprotein IIb/IIIa receptor, which prevents MW 5.8kDa; Only ~15-25% has pentasaccharide seq binding of adhesive glycoproteins (fibrinogen, von Willebrand necessary for activity; Excreted primarily by kidneys factor, etc) to surface of activated platelets (This is the Final More predictable response than UFH b/c better bioavail, Common Pathway of Platelet Aggregation); Specific for longer ½ life, & dose-indep cl; can be used w/out monitoring, GPIIb/IIIa; no antibody response; used only in hospital for long-term prophylaxis in certain pts Rapid onset; Activity lasts for ~4h; elimination by renal Adverse effects: Major bleeding,, HIT (less common than primarily UFH); Rx of OD: protamine (neutralizes anti-IIa completely Adverse effects: bleeding (usu at site of arterial access), & Xa partially) & Withdrawal of drug thrombocytopenia NOT INTERCHANGEABLE w/ other LMWHs or UFH Anticoagulant Anticoagulant – Inhibits Xa only Inhibits Xa & IIa (thrombin) & most proteolytic coag Synthetic pentasaccharide binding sequence enzymes, but different types have different specificity; Excreted primarily by kidneys; once a day dosing Enhances activity of tissue factor pathway inhibitor (TFPI) Produces more predictable response than UFH b/c better Found normally in mast cells & CT; has high density of “-“ bioavail, longer ½ life, & dose-indep cl; can be used w/out charges; effective both in vivo (esp venous clots) & in vitro; monitoring, for long-term prophylaxis in certain pts Needs pentasaccharide seq & antithrombin present for activity Adverse effects: Major bleeding,, heparin-induced Parenteral b/c enteral sulfatases remove “-“ charges thrombocytopenia (rare) Onset immediate (iv) or 1-3h (UFH), 3-6h (LMWH) or 17-21 Rx of OD: Withdrawal of drug (Protamine does not h (Fondaparinux) when SC; never IM (hematoma results) reverse) TRANSFUSIONS NOT EFFECTIVE IN RX OF OD!! Direct irreversible inhibitor of thrombin, including clot Warfarin antagonist bound thrombin (doesn’t req antithrombin) Active form of Vit K that can be used by vit K-dependent Substitute for Heparin when HIT is present enzyme γ-carboxylase to convert glutamic acid residues on II, Recombinant derivative of hirudin (anti-coag in leeches) VII, IX, X, Protein C & S by γ -carboxylation to Gla (γ Admin iv (0.4mg/kg bolus followed by 0.15mg/kg/hour -carboxyGlu) form, enabling the clotting factors to bind to Ca, infusion aimed at achieving aPTT ratio of 1.5-2.5 which forms the bridge to platelets, anchoring them to the site No effective antidote but has short ½ life; cleared by renal of injury; acts only in vivo not in vitro excretion (t 1/2 ~1.3 h) (so affected by renal impairment Used to treat OD of warfarin, but if therapy is too vigorous, unlike argatroban) this may complicate re-establishment of warfarin therapy Immunogenic - Anaphylaxis has been observed in pts treated since K1 has a long duration of action again w/in 3 months of previous exposure

Heparin Antagonist Fibrinolytic (Thrombolytic) Non-glycosylated deletion mutant of wild type tPA Developed to have a longer half-life and to act faster & better penetrate a thrombus than Alteplase Bolus 2X 30 min apart; ½ life of 13-16 min

Used to treat overdose of UFH (completely reverses) & neutralizes the anti-IIa activity of LMWH (such as enoxaparin, dalteparin, tinzaparin), but only partially reverses the anti-Xa activity Anaphylactoid rxns are possible, so infuse slowly DOES NOT REVERSE FONDAPARINUX

Streptokinase

Tenecteplase

(Streptase, Kabikinase)

Ticlopidine

(TNKase)

Tinzaparin

(Ticlid )

(Innohep )

Tirofiban Tranexamic Acid (Aggrasta t)

Urokinase

(Breokinase, Abbokinase)

Unfractionated Heparin (UFH)

(Cyklokapron)

Warfarin sodium

(Coumadin)

UFH vs LMWH & Fondaparinux

Fibrinolytic (Thrombolytic) Fibrinolytic (Thrombolytic) 6 amino acids substituted at 3 sites compared to wild type tPA Binds to plasminogen thereby converting plasminogen into a These mutations prolong plasma ½ life & increases fibrin plasmin-like molecule capable of converting plasminogen to plasmin specificity & resistance to plasminogen activator (i.e. indirect plasminogen activation) inhibitor-1 iv or ic infusion; ½ life of 23-29 min; antigenic; results in less Less non-intracranial major bleeding episodes than accelerated tPA; patency at 90 min than alteplase, reteplase, or tenecteplase not antigenic; results in more patency at 90 min than streptokinase; Can cause proteolytic destruction of blood clotting factors (lytic direct plasminogen activation state), which occurs when plasminogen is activated in the blood Single bolus administration; ½ life of 20-24 min stream b/c it does not require fibrin for activity

Low Molecular Weight Heparin w/ Anti-Xa:Anti-IIa ratio of 1.9(UFH undergone enzymatic or chem depolymerization) MW 5.8kDa; Only ~15-25% has pentasaccharide seq necessary for activity; Excreted primarily by kidneys Produces more predictable response than UFH b/c better bioavail, longer ½ life, & dose-indep cl; can be used w/out monitoring, for long-term prophylaxis in certain pts Adverse effects: Major bleeding,, HIT (less common than UFH); Rx of OD: protamine (neutralizes anti-IIa completely & Xa partially) & Withdrawal of drug NOT INTERCHANGEABLE w/ other LMWHs or UFH

Antiplatelet Agent – ADP Pathway Inhibitor Irreversibly blocks purinergic receptor (P2Y12 )for ADP, so indirectly inhibits the binding of fibrinogen to platelet receptor GPIIb/IIIa ; Well absorbed from GI (better bioavail w/ food); metabolized to active form in liver; std dose (250mg/BID), max inhibition of platelet fxn 3-5 days; takes ~5d after cessation for plt fxn to return to nl; Adverse: diarrhea, rash (> ASA), abd pain, dyspepsia, GI bleeding (< ASA); bleeding in pts. on anti-coag; bone marrow suppression (neutropenia ~1%, aplastic anemia), thrombotic thrombocytopenic purpura; Antacids absorption & cimetidine metabolism

Hemostatic

Antiplatelet Agent – GPIIb/IIIa Antagonist Tyrosine derivative (non-peptide) that prevents platelet aggregation Binds reversibly to plasminogen and thereby blocks the binding of by binding to the platelet glycoprotein IIb/IIIa receptor, which plasminogen to fibrin & its activation and transformation to plasmin prevents binding of adhesive glycoproteins (fibrinogen, von Willebrand factor, etc) to surface of activated platelets (This is the Useful in enhancing hemostatic when fibrinolysis contributes to Final Common Pathway of Platelet Aggregation); Specific for bleeding, but not FDA approved for bleeding accompanying GPIIb/IIIa; No antibody response; only used in hospital; Rapid fibrinolytic use onset; Activity lasts for ~4-8h; Elimination renal ; Adverse effects: Contraindicated in patients with DIC bleeding (usu at site of arterial access), thrombocytopenia

Oral & Parenteral Anticoagulant ; formation of clotting factors II,VII, IX, X, protein C & S b/c require Vit K (drug inhibits KO Fibrinolytic (Thrombolytic) reductase (major effect) & K reductase, which converts vit K to Proteolytic enzyme that converts plasminogen to plasmin directly active form); Prevents γ -carboxyglutamic acid residues (Ca binding Has a half-life of 14-20 minutes sites) from being added, so can’t bind to platelets; Major disadv: latent period (long onset & peak effect); Not used in HIT b/c assoc Can cause proteolytic destruction of blood clotting factors (lytic w/ venous limb gangrene or multicentric skin necrosis (def protein C state), which occurs when plasminogen is activated in the blood which is thrombotic); Adverse effects: bleeding (risk h esp if hx of stream b/c it does not require fibrin for activity GI bleeding); recurrent skin necrosis (thrombosis of venules/ capillaries of SC fat); OD Rx: plasma transfusion & Vit K1

LMWH & Fondaparinux has a more predictable anti-coag response ( binding to plasma proteins & proteins released from activated platelets & endothelial cells); better bioavail at low doses ( binding to endothelium); dose-indep clearance mech & half-life ( binding to macrophages) None of them need monitoring when used prophylactically (except in pts w/ renal insuff & pts weighing <50kg or >80kg), but UFH needs aPTT (1.5-2.5 aPTT) or plasma heparin concentrations (via antifactor Xa assay w/ TI levels .3-/7IU/mL or protamine titration) during treatment

Anticoagulant - Inhibits Xa & IIa –thrombin equally GAG from bovine lung or porcine gastric mucosa; Variable MW; must be standardized (unit base dosing); Only ~1/3 has necessary pentasaccharide seq for activity; Endothelial cells & macrophages clear (rapid & dose depend) & much slower renal 1st order mech; binds to several plasma proteins (makes inactive) = nonlinear resp (both intensity & duration disproportionally w/ dose); ½ life dose depend Adverse effects: major bleeding, osteoporosis (prolonged use, preg women), heparin-induced thrombocytopenia (HIT) Treatment of OD: withdrawal (usu sufficient), protamine

Heparin-induced thrombocytopenia (HIT) (Note: Type 1: Benign transient, so information is for Type 2, which is more severe)

Citrate

Oxalate

Recombinant activated coagulation factor VII (rFVIIa) (NovoSeven)

Treatment of venous thromboembolism

Treatment of unstable angina

Anticoagulant prophylaxis in moderate-risk or high risk patients

Indicated in Heparin-induced thrombocytopenia with thrombosis

Used in angioplasty

Factors that determine pt’s response to oral anticoagulants

Chelating Agent Binds Calcium Used in vitro only (blood storage) to prevent clotting

Hemostatic Treatment of bleeding episodes in hemophilia patients with inhibitors (antibodies) to factor VIII or IX Currently being used “off-label” to stop bleeding in pts w. intracerebral hemorrhage (hemorrhagic stroke) & other instances of uncontrolled bleeding (major trauma)

Occurs when pts dev antibodies (IgG) against complexes of UFH & platelet factor 4 that activates platelet FcγRIIa receptors & plt count 50% or more; Occurs 5-10dys after 1st exposure or w/in 24hrs of admin if prior exposure, esp if prior exposure w/in the past 100dys; Occurs w/ bovine lung > porcine mucosal heparin; iv> SC; UFH > LMWH >> Fondaparinux; Pt w/ highest risk are postoperative orthopedic, cardiac & vascular surgery pts getting UFH for 1-2 wks; danger is b/c assoc w/ DVT, DIC, PE, cerebral thrombosis, MI & ischemic injury to legs or arms (White Clot Syn); Rx: Change therapy to lepirudin or argatroban

Chelating Agent Binds Calcium Used in vitro only (blood storage) to prevent clotting

Use in intracerebral hemorrhage has been assoc. w/ serious thromboembolic adverse events (myocardial or cerebral infarction)

UFH (when rapid reversal is important)

UFH (when rapid reversal is important)

Enoxaparin

Enoxaparin

Dalteparin

Dalteparin

Bivalirudin

Tinzaparin

Lepirudin

Enoxaparin – moderate or high risk Dalteparin – moderate or high risk Tinzaparin – moderate or high risk

Argatroban

Fondaparinux – high risk only Warfarin

Vitamin K levels ( intake= warfarin effect) – inadequate diet, fat malabsorption = vit K; lots of green veggies & supplements w/ high K = vit K Liver dz , Elderly, Congestive heart failure (results in hepatic congestion) or Slow metabolizers due to CYP2C9 & VKORC1 (vit K epoxide reductase complex subunit 1) – metabolism = warfarin effect Infection, following surgery, hypermetabolism – increases sensitivity to warfarin Significant interactions can occur when any drug is added or removed

Bivalirudin

Drugs that will potentiate warfarin effects (These are the specific ones Dr. Benz said to know)

Drugs/foods that will inhibit warfarin effects (These are the specific ones Dr. Benz said to know)

Contraindications to Anticoagulant, Fibrinolytic Therapy, & Glycoprotein IIb/IIIa Antagonists

Therapy Recommendations for Treatment of DVT

Therapeutic Uses of Fibrinolytic Agents

Adverse effects of Fibrinolytic Therapy

Aspirin Doses

Indications for Clopidogrel & Ticlopidine

Indication for Glycoprotein IIb/IIIa Antagonists (GPIs) (Abciximab, Eptifibatide, Tirofiban)

Barbiturates

Amiodarone (nonselective for enantiomer)

Cholestyramine

Fluconazole (selective for S enantiomer)

High Vitamin K content of foods/enteral feeds

Omeprazole (selective for R enantiomer

Absolute: Active bleeding; Severe bleeding diathesis or platelet count <20,000/mm3; Neurosurgery, ocular surgery, or intracranial bleeding w/in past 10 days; pregnancy Relative: Mild-to-moderate bleeding diathesis or thrombocytopenia, brain metastases, recent major trauma, major abd surgery w/in INR necessary for most conditions is 2.0-3.0 EXCEPT for past 2 days; GI or GU bleeding w/in past 14 days, mechanical prosthetic heart valves, which are high risk, has a endocarditis, severe HTN (SBP>200, DBP>120 or both) at recommended INR of 2.5-3.5 presentation 1) Use heparins immediately b/c they have rapid onset of action 2) Administer warfarin at same time as heparin 3) Do not discontinue heparin until the INR indicates that warfarin is effective (~5days usually)

Bleeding (esp intracranial hemorrhage (streptokinase
Prophylaxis before (300-600mg, 4-6h) and after (75mg.d, 912months) for percutaneous coronary intervention (PCI) in combination w/ aspirin Also used in acute coronary syndrome (ACS-unstable angina or non-ST segment elevation MI or non-Q wave MI), post MI prophylaxis, & for stroke prevention in pts w/ transient ischemic attacks (TIA) or previous thrombotic stroke (Pts on clopidogrel+ASA & scheduled for CABG should d/c the clopidogrel 5-7 days before surgery otherwise at increased risk for major bleeding)

Acute myocardial infarction (primary angioplasty is better if available), clots of PE & DVT, acute peripheral artery thrombosis, acute ischemic stroke (alteplase) Can reduce mortality significantly, most effective when used shortly after thrombus formation since recently formed thrombi are easier to lyse than aged (cross-linked thrombi); Venous thrombi easier to lyse than arterial thrombi; Concomitant admin of ASA & iv UFH can be used; bolus agents permit admin by emergency personnel outside of hospital Prevention of recurrent MI, MI in pts w/ unstable angina, or MI & death in pts. w/ stable angina: 75235 mg Qday; Prevention of vascular mortality in suspected MI: 160-162.5 mg ASAP, continued for 30 days then consider continued use; Post-revascularization w/ CABG: 325mg starting 6hrs post-procedure & cont 1 yr; PTCA: 325mg 2hrs pre-surgery, then 160-325mg daily; Carotid endarterectomy: 80mg Qday to 650mg BID pre-surgery & cont indef; Prevention of death & recurrent stroke following TIA or ischemic stroke: 50-325 mg Qday; Analgesic & antipyretic: 650mg; Anti-inflammatory: Up to 4g/d Adjunct in pts w/ ischemic heart dz undergoing or abt to undergo PCI w/ or w/out stenting or thrombolysis In low to intermediate risk pts, who have previously received aspirin & clopidogrel, GPI’s appear to offer no additional benefit In high risk pts (those w/ ACS, recent MI, bypass-graft stenosis, chronically occluded coronary arteries, or angiographically visible intracoronary thrombus), aspirin, clopidogrel and GPI’s are indicated.

Beta blockers

Angiotension Converting Enzyme Inhibitors

Loop Diuretics

Sodium nitroprusside

Spironolactone Angiotensin Receptor Blockers (Aldactone ) Hydralazine Eplerenone (BiDil – hydralazine +Isosorbide dinitrate) (Apresoline )

Carvedilol

(Inspra)

Thiazide Diuretics

(Coreg)

Antihypertensive & for Heart Failure Most are prodrugs that inhibit conversion of angiotensin I to angiotensin II Increases plasma renin activity, but decreased angiotensin II levels ( vasoconstriction & aldosterone) Decreases PVR, no change in HR, decreases preload and afterload Decreases symptoms of heart failure & increased survival

β receptor adrenergic antagonists Rx: antihypertensive, antianginal & heart failure O2 demand effects: decreased - HR, systemic BP, & contractility, increased by LVEDV; O2 delivery effects: some redistrib blood flow to ischemic areas Sudden withdrawal – exacerbation of angina MI possible May worsen heart failure initially & improvement may take months DO NOT USE IN VASOSPASTIC ANGINA

Arterial & venous dilator Blocks NaCL reabsorp in TAL by inhibiting Na-K-2Cl symporter; Stim. guanylyl cyclase cGMP either release of In pts. w/ heart failure, preload. & improvement in pulmonary NO or by direct stimulation of the enzyme congestion –beneficial in acute pulm but effects on survival unk. Continuous iv infusion; rapid onset & offset of Edema; urinary Ca excretion ( Ca reabsorption in ascending limb) action = close monitoring necessary Rx for HTN, hypercalcemia, heart failure Aq. solution photosensitive Adverse effects: hypokalemia (cardiac arrhythmias, potentiates Elimination: Na2Fe(CN)5NO CN SCN urine effects of digitalis), metabolic alkalosis, hyperuricemia, Adverse effects: Hypotension, Cyanide & thiocyanate toxicity hyperglycemia, some lipid h, volume depletion, hyponatremia, Used in hypertensive emergencies (caution in pts w/ intracranial ototoxicity, allergic rxn. pressure or azotemia) and in heart failure ( preload & afterload)

K-Sparing Diuretic - Mineralocorticoid Receptor Antagonist Synthetic steroid that binds to cytoplasmic aldo receptor, preventing binding of aldo which Na reabsorption and K & H secretion in pressor response to infused angiotensin I & II; plasma renin late DT & CD activity & plasma angiotensin II levels Rx: dz states assoc. w/ plasma aldo levels (1º & 2 º Adverse effects: Hypotension (esp if vol depleted), dizziness (low hyperaldosteronism), nephrotic syndrome, heart failure (low dose freq of hospitalization & mortality – must monitor serum K & incidence), K+ can occur, angioedema (less freq than w/ ACE renal fxn), cirrhosis w/ ascites & in combo w/ thiazide or loop inhibitors), BUN & Cr in pts w/ bilateral RAS (same as ACE diuretics in pts w/ edema & hypertension inhib), fetal toxicity & birth defects (same as ACE inhib), less likely Adverse effects: Hyperkalemia, metabolic acidosis (possible), to cause cough other endocrine effects (gynecomastia in males) Inhibits type 1 angiotensin II receptors (AT1)

K-Sparing Diuretic - Mineralocorticoid Receptor Antagonist

Arterial vasodilator via direct relaxation PVR ( afterload) & lowers BP, but activates compens. resp. Selective synthetic steroid binds to cytoplasmic aldo receptor, (sympathetic stim, salt & water retention) preventing binding of aldo which Na reabsorption & K & H Can use w/ β-blocker & diuretic, or w/ organic nitrate in Africansecretion in late distal tubule & collecting duct American pts w/ heart failure Used to treat dz states assoc. w/ plasma aldo levels (1º & 2 º Oral & iv administration, but metabolized partly by acetylation hyperaldosteronism) & in combo w/ thiazide or loop diuretics in pts Adverse effects: Palpitations, angina, headache, drug-induced lupus w/ edema & hypertension; recently approved for heart failure (greatest in slow acetylators), fluid retention following acute MI in certain cases Adverse effects: Hyperkalemia, metabolic acidosis (possible)

Mixed β rel="nofollow">α1 receptor antagonist & Antihypertensive agent Blocks salt reabsorption in distal convoluted tubule (DCT) inhibiting High lipid solubility & metabolized by liver & kidneys NaCl symporter in luminal membrane PVR & often reduces Rx: HTN & heart failure in certain pts ( freq of hospitalizations & urinary calcium excretion mortality) Rx: HTN, idiopathic hypercalciuria, heart failure (effect on survival Adverse effects: myocardial contractility, bradyarrhythmias, unk, preload, congestive symptoms) bronchospasms, prolong hypoglycemia in pts taking insulin, Unlikely to be effective if GFR <30mL/min triglycerides, HDL-cholesterol, fatigue, sleep disturbance, Adverse: Hypokalemia, metabolic alkalosis, hyperuricemia, depression, hypertensive response in some situations hyperglycemia, some lipid , vol depletion, hyponatremia, allergic (pheochromocytoma), sudden withdrawal – exacerbation of rxn., NOT assoc. w/ ototoxicity angina esp if MI has occurred Less effect than loop diuretics but greater than K-sparing NSAIDS may reduce BP lowering effect

Dopamine

Dobutamine

(Dobutrex)

Calcium channel blockers

Metoprolol

(Lopressor, Toprol XL)

Nifedipine

Propranolol

(Inderal)

Diltiazem

Nitroglycerin

(Nitrostat, Nitrodur)

Isosorbide dinitrate

(BiDil – hydralazine +Isosorbide dinitrate) (Isordil Titradose, Dilatrate-SR, Isochron)

Isosorbide-5-mononitrate

(Imdur, Monoket)

DAergic neurotransmitter Can produce renal vasodilation due to presence of DA receptors in kidney vessels Does not cross BBB Controls motor activity in caudate-putamen area of brain Associated w/ positive reinforcement in limbic area of brain Used parenteral in heart failure b/c positive inotrope

Selective β1 receptor agonist May increase cardiac output with less reflex tachycardia than occurs with nonselective β agonists such as isoproterenol Short term iv infusion w/ rapid onset & ½ life ~2 minutes Used parenteral in heart failure b/c positive inotrope Adverse effects: Excessive increase in heart rate, arrhythmias, & other

β1 receptor antagonist - Cardioselective (β 1>>> β 2) Interacts with L-type Ca channels to cellular uptake of Ca2+. Produces local anesthetic effect, has moderate lipid solubility, & Some also block other cardiac ion channels metabolized by liver Decreases O2 demand ( HR, & mycoardial work) and increases O2 Rx: HTN & heart failure ( freq of hospitalizations & mortality) supply (vasodilate coronary a) Adverse effects: contractility, bradyarrhythmias, prolong Classes: phenylalkylamine, dihydropyridine, & Benzothiazepines hypoglycemia in pts taking insulin, bronchospasms, sleep disturb, Rx: HTN, angina, certain cardiac arrhythmias triglycerides, HDL-cholesterol, fatigue, depression, hypertensive Vasodilation (mainly arterial), some classes HR via sinus node response w/pheochromocytoma, sudden withdrawal – exacerb of pacemaker rate, some classes AV conduction, all classes angina esp if MI has occurred contractility NSAIDS may reduce BP lowering effect All classes have large 1st pass effect

1,4-Dihydropyridine Ca Channel Blocker w/ Oral admin High vascular selectivity (ratio of vasc to cardiac effects) = sympathetic reflex & contractility but vasodilation & SNS activation tends to counter this results in BP, PVR Rx: HTN, angina (atherosclerotic & vasospastic) Adverse effects: dizziness, hypotension, headache, flushing, constipation, peripheral edema, aggravation of ischemia, MI w/ immed release due to SNS reflex. Rare: bradycardia, AV block, cardiac arrest, heart failure

Nonselective β blocker & Antiarrhythmic Class II HR & contractility CO; mb stabilization; renal renin release; CNS effects not major (although used for stage fright) Produces local anesthetic, high lipid sol., & metabol by liver Adverse effects: myocardial contractility, bradyarrhythmias, bronchospasms, prolong hypoglycemia in pts taking insulin, Triglycerides, HDL-cholesterol, fatigue, sleep disturbance, depression, hypertensive response in some situations (pheochromocytoma), sudden withdrawal –exacerbation of angina esp if MI has occurred NSAIDS may BP lowering effect

Benzothiazepine Ca Channel Blocker w/ Oral or iv admin Organic Nitrate - Releases NO endothelium cGMP prod Lower vascular selectivity (ratio of vasc to cardiac effect) than Available as short-acting (sublingual– rapid onset) & long-acting diphydropyridines (=less sympathetic reflex), AV conduction, (oral– sign. 1st pass metabolism, ointment, patch, buccal); also available in a lingual spray & iv sinus node pacemaker rate HR & contractility results in Relaxes veins, some arterial, & other smooth muscles (esophageal, BP, PVR, HR biliary tract) and has an antiplatelet effect Rx: HTN, Angina (atherosclerotic & vasospastic), supraventricular Rx: relieve acute attacks (sublingual tabs) & prophylaxis of chronic tachyarrhythmias effort-assoc angina and effective in vasospastic angina Adverse effects: dizziness, hypotension, headache, flushing, Adverse effects: headaches, orthostatic hypotension, rashes constipation, peripheral edema. Rare: aggravation of ischemia, occasionally. Sildenafil, tadalafil, & vardenafil worsens hypotensive bradycardia, AV block, cardiac arrest, heart failure effects CAN INCREASE PLASMA DIGOXIN LEVELS

Organic Nitrate - Releases NO endothelium cGMP prod Organic Nitrate - Releases NO endothelium cGMP prod Available as short-acting (sublingual) & long-acting (oral – ~100 st Available as long-acting (oral– sign. 1 pass metabolism) bioavailability, chewable oral, sublingual) Relaxes veins, some arterial, & other smooth muscles (esophageal, Relaxes veins, some arterial, & other smooth muscles (esophageal, biliary tract) and has an antiplatelet effect biliary tract), preload, antiplatelet effect Rx: Prophylaxis of chronic effort-assoc angina & Rx: chronic effort-assoc angina (acute & prophylaxis) & vasospastic effective in vasospastic angina angina, heart failure w/ hydralazine in Afircan-Americans Adverse effects: headaches, orthostatic hypotension, Adverse effects: headaches, orthostatic hypotension, rashes rashes occasionally. Sildenafil, tadalafil, & vardenafil worsens occasionally. Sildenafil, tadalafil, & vardenafil worsens hypotensive hypotensive effects effects

Ranolazine Digoxin immune fab (ovine) (Ranex a)

1,4-Dihydropyridines

Nesiritide

Adverse effects of Digitalis

Digoxin

Factors that increase risk of digitalis toxicity

Quinidine

Cardiac glycosides

Milrinone

New oral drug for chronic angina – Mech of action unknown Fab Antibody Fragment derived from sheep that binds to digoxin Used in overdose of digoxin to reverse toxicity effects

Recombinant human B-type natriuretic peptide (hBNP) Approved for use in certain pts w/ acute decompensated heart failure Decreases pulmonary capillary wedge pressure & dyspnea Mech involves action on particulate guanylate cyclase receptor increased cGMP smooth muscle relaxation Iv admin (pharmacokinetic ½ life ~18 min but pharmacodynamic ½ life longer than this would predict – hypotension may last hrs), clearance receptors on cells Adverse effects: Hypotension, significant renal damage & deaths

Reserved for pts who have not achieved an adequate response w/ other antianginal drugs and should be used in combo w/ amlodipine, beta-blockers or nitrates Little effect on HR or BP, effects less in women Extens metabolized mainly by CYP3A; also P-glycoprotein substrate Adverse effects: dizziness, headache, constipation, nausea, Prolong QT interval

Class of Ca Channel Blocker - Ex) Nifedipine, Amlodipine, Felodipine, Isradipine, Nicardipine, Nimodipine, Nisoldipine High vascular selectivity (ratio of vasc to cardiac effects) = sympathetic reflex & contractility but vasodilation & SNS activation tends to counter this results in BP, PVR Rx: THN, angina (atherosclerotic & vasospastic)

Rx: heart failure ( symptoms, hospitalizations) & supraventricular tachyarrhythmias (atrial fib & flutter) Cardiac arrhythmias such as: atrial tachycardia w/ AV block, AV Inhibits Na,K-ATPase pump in heart to contractility b/c Ca block (1st, 2nd, or 3rd degree), AV junctional rhythm, vent premature inside cell; Vagal efferent act, HR, atria ERP & contractility, contractions (ex bigeminy), vent tachycardia, vent fibrillation Other: anorexia, nausea & vomiting, diarrhea, blurred vision, & AV conduction ( ERP and conduct vel.) abnormal color vision (yellow/green halos), confusion, other OD Rx: Stop drug, serum K management, arrhythmia & heart block mental disturbances (These may be warning signs of toxicity management, & role of digoxin immune fab (ovine) before arrhythmias) Admin oral or iv. Cl reduced in renal insufficiency DI: thiazide or loop diuretics (hypokalemia binding); quinidine, Delayed afterdepolarizations, arrhythmias, heart block possible; SNS outflow may occur verapamil or amiodarone ( concentration), antacids, kaolin-pectin, cholestyramine ( concentration)

Antiarrhythmic Class IA Rx: Atrial fib & flutter, serious vent arrhythmias Blocks activated Na channels ( conduction velocity) & K Hypokalemia (enhances binding of digitalis to Na,K-ATPase pump) channels ( AP duration ERP). Also α blockade, antimuscarinic Hypercalcemia Hypomagnesemia & antivagal (may cause paradoxical vent rate in pts w/ atrial Renal insufficiency (most drug is cleared unchanged by kidneys) flutter). Hepatic & some kidney metabolism Adverse effects: torsades de pointes ( QT interval) (even at TI Drugs: thiazide or loop diuretics, quinidine, verapamil, or dose), diarrhea, cinchonism (headache, tinnitus), hypersensitivity ( amiodarone, nitroglycerin platelets, hepatotoxicity) DI: phenytoin or phenobarbital ( quinidine), digoxin level, can inhibit CYP2D6

Inhibits cAMP phosphodiesterase (rel selective for type III) g cAMP g h contractility & vasodilation (arterial & venous) Effects in pts w/ heart failure: pulmonary capillary wedge pressure, PVR, cardiac output Used only intravenously & only for acute heart failure or for severe exacerbation of chronic heart failure Adverse effects: arrhythmias, other

Class of drug used in treating heart failure & supraventricular tachyarrhythmias such as atrial fib & flutter Digoxin = only one avail in US Inhibits Na,K-ATPase pump in heart to contractility Binding to Na, K-ATPase is enhanced by low extracellular K and results in avail of Ca at level of contractile element Vagal efferent activity, which tends to HR & AV conduction and Decreases SNS activity

Lidocaine Disopyramide (Xylocain (Norpace)

Mexiletine

e)

Flecainide

(Mexitil)

(Tambocor)

Bretylium Propafenone (Bretylol (Rythmol)

Sotalol

)

Dofetilide

(Betapace)

Ibutilide

(Tikosyn)

Adenosine

(Corvert)

Antiarrhythmic Class IA Amide anesthetic (most common in US) & Antiarrhythmic Class IB Use: Serious ventricular arrhythmias Uses: Topical, IV regional, Spinal, & Epidural anesthesia, serious Blocks activated Na channels ( conduction velocity) & K ventricular arrhythmias channels ( AP duration ERP, assoc w/ QT interval). Also Blocks activated & inactivated Na channels ( effect in blockade of antimuscarinic & antivagal (may cause paradoxical depolar/ischemic cells) – conduction velocity ventricular rate in pts w/ atrial flutter effects) & neg inotropic effect pKa 7.7, pH sol 5.6 (w/out Epi) w/ Rapid onset, intermed duration, ( contractility) intermediate toxicity Not used orally b/c 1st pass; clearance by liver Oral admin, hepatic metabolism, urinary excretion dz, heart failure, propranolol Adverse effects: ventricular tachycardia, torsades de pointes, Least cardiotoxic of current Na channel blockers, but adverse effects decreased myocardial contractility can precipitate or worsen heart inc. tremor, altered consciousness, seizures (above TI) failure, constipation, anticholinergic effects

Antiarrhythmic Class IC Use: Maintenance of sinus rhythm in certain supravent arrhythmias in pts w/out structural heart dz Blocks Na & K channels (doesn’t prolong AP b/c AP shortened in Purkinje cells & lengthened in vent cells), myocardial contractility Oral admin, elim. by renal excretion & hep metabolism Adverse effects: blurred vision, can worsen heart failure, can cause or exacerbate potentially fatal arrhythmias (cause heart block), CAST experiment found h mortality in post-MI pts w/ premature vent contractions

Antiarrhythmic Class IB Use: Serious ventricular arrhythmias Orally effective lidocaine analog Blocks activated & inactivated Na channels ( effect in depolar/ischemic cells) – conduction velocity Adverse effects: tremor, nausea, other Low association w/ causing antiarrhythmias

Antiarrhythmic Class IC Antiarrhythmic Class III Use: Refractory life-threatening ventricular arrhythmias Use: supraventricular arrhythmias AP duration & ERP in ventricle by blocking K channels; interferes Blocks Na channels and β channels, myocardial contractility, w/ NOR release (initially releases NOR) Iv admin HR Adverse effects: Can exacerbate arrhythmias & cause some nonAdverse effects: hypotension, orthostatic hypotension, arrhythmias cardiac effects

Antiarrhythmic Class III Use: Maintenance of nl sinus rhythm in pts w/ atrial fib/flutter; conversion of atrial fib AP duration (blocks K channel), blocks rapid component of the delayed rectifier K current; QT interval Oral admin & renal>hepatic metabolism; renal secretion by organic cation system Adverse effects: torsades de pointes, hospital & prescribers must participate in education programs in order for drug to be available; drug interactions

Use: Conversion of paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm Acts on adenosine receptors (effects similar to stimulation of ACh receptors); AV conduction; ERP in AV node ½ life <10sec, rapidly taken up & metabolized; rapid iv admin Adverse effects (usu transient due to short ½ life): facial flushing, headache, hypotension, arrhythmias, heart block, asystole (transient or prolonged), dyspnea, chest discomfort DI: methylxanthines (caffeine, theophylline)- inhib receptors ( effect); dipyridamole- adenosine uptake inhib ( effect)

Antiarrhythmic Class III Use: serious vent arrhythmias, maintenance of sinus rhythm in pts w/ atrial fib/flutter who are currently in sinus rhythm D & L isomers both AP duration (block of K channels); QT interval.; L isomers HR, conduction velocity AV node, & refractoriness of AV node Oral admin & renal excretion Adverse effects: adv effects of beta blockade ( HR, myocardial contractility), torsades de pointes

Antiarrhythmic Class III Use: Rapid conversion of atrial fib or flutter to sinus rhythm AP duration (blocks K channel), blocks rapid component of the delayed rectifier K current; delays repolarization by inward Na current (Na agonist), QT interval Admin iv & hepatic metabolism Adverse effects: torsades de pointes

Esmolol

Classic Angina

Amiodarone Variant Angina (Cordaron e)

Sildenafil (Not bolded in notes)

Organic Nitrates

(Viagra) Vardenafil (Not bolded in notes) Procainamide (Levitr a) Tadalafil (Not bolded in notes)

Drugs you give to decrease AV conduction to slow ventricular rate (Ciali

s)

AKA Atherosclerotic Angina, Effort-Associated Angina

β blocker & Antiarrhythmic Class II

Use beta blockers, Ca channel blockers & organic nitrates to treat

Cardioselective drug w/ short ½ life; used iv

Antiarrhythmic Class III Use: Serious vent arrhythmias, effective in certain supravent arrhythmias; iv form for acute (vasodilation freq) AP duration (blockade of K+; ERP; QT interval), Na & Ca channel block; antiadrenergic & anticholinergic effects; Oral (bioavail 35-65%), elim by liver (½ life = weeks) Adverse: HR , AV block (pts w/ nodal dz), pulmonary fibrosis, hypo or hyperthyroidism, corneal microdeposits, visual acuity, skin blue-gray discoloration, AST/ALT, peripheral neuropathy, can worsen arrhythmias (torsades de pointes rel uncommon), DI w/ warfarin & digoxin

AKA Vasospastic angina Use Ca channel blockers & organic nitrates to treat

O2 demand effects: Phosphodiesterase 5 inhibitor Inhibition of phosphodiesterase 5 inhibitor prevents breakdown of cGMP into GMP, so cGMP Rx: Erectile dysfunction CI: in pts using organic nitrates (increases hypotensive effect)

Phosphodiesterase 5 inhibitor Inhibition of phosphodiesterase 5 inhibitor prevents breakdown of cGMP into GMP, so cGMP Rx: Erectile dysfunction CI: in pts using organic nitrates (increases hypotensive effect)

Digoxin Beta blocker Ca channel blocker

LVEDV, systemic BP, HR & contractility via sympathetic reflex O2 delivery effects: some coronary a. dilation, some redistrib blood flow to ischemic areas, LVEDV may subendocard perfusion, relieves coronary spasms Adverse effects: Headaches, Orthostatic hypotension, sildenafil, tadalafil, & vardenafil increases hypotensive effect so CI, rashes occasionally Tolerance dev to effects if continuous expos – provide drug free period of min of 8 hrs every day

Antiarrhythmic Class IA Rx: Serious ventricular arrhythmias Blocks activated Na channels ( conduction velocity) & K channels ( AP duration ERP, assoc w/ QT interval). Oral or iv admin. Urinary excretion & hepatic metabolism (major metabolite is N-acetylprocainamide (NAPA) can also h AP duration & excreted in urine) Adverse effects: New arrhythmias (inc. torsades de pointes) can occur, hypotension (ganglionic blockade), marked slowing of conduction, nausea, drug-induced lupus (lg. % dev +ANA w/ long term use, but not all dev lupus), agranulocytosis

Phosphodiesterase 5 inhibitor Inhibition of phosphodiesterase 5 inhibitor prevents breakdown of cGMP into GMP, so cGMP Rx: Erectile dysfunction CI: in pts using organic nitrates (increases hypotensive effect)

Benzothiazepines

Phenylalkylamine

Atorvastatin

Verapamil

(Lipitor)

Orlistat Fenofibrate (Xenic (Tricor)

Cholestyramine

al)

Fluvastatin

(Questran)

(Lescol)

Pravastatin Clofibrate (Pravacho l)

(Atromid-S)

Class of Ca Channel Blocker - Ex) Verapamil

Class of Ca Channel Blocker - Ex) Diltiazem

Lower vascular selectivity (ratio of vasc to cardiac effect) than Lower vascular selectivity (ratio of vasc to cardiac effect) than diphydropyridines (=less sympathetic reflex), AV conduction, diphydropyridines (=less sympathetic reflex), AV conduction, sinus node pacemaker rate HR & contractility results in sinus node pacemaker rate HR & contractility results in BP, PVR, HR BP, PVR, HR Rx: Angina, supraventricular tachyarrhythmias (ex atrial fibrillation)

Rx: Angina, supraventricular tachyarrhythmias (ex atrial fibrillation)

Phenylalkylamine Ca Channel Blocker w/ Oral or iv admin Competitive inhibitor of HMG CoA reductase Lower vascular selectivity (ratio of vasc to cardiac effect) than liver cholesterol synthesis, which liver LDL receptor production, diphydropyridines (=less sympathetic reflex), AV conduction, which plasma LDL clearance – Major use LDL cholesterol & ERP of Av node, sinus node pacemaker rate HR & Reduces risk for CHD & stroke contractility results in BP, PVR, HR LDL by 18-55%, HDL 5-15%, Triglycerides 7-30% Rx: HTN, angina (atherosclerotic & vasospastic), supraventricular Adverse effects: Myopathy, AST& ALT (both dose-related tachyarrhythmias Absolute CI: active or chronic liver dz, pregnancy Adverse effects: dizziness, hypotension, headache, flushing, Relative CI: Concomitant use of cyclosporine, macrolide constipation, peripheral edema. Rare: aggravation of ischemia, antibiotics, various anti-fungal agents, & CP450 inhibitors (fibrates bradycardia, AV block, cardiac arrest, heart failure & nicotinic acid should be used w/ appropriate caution) CAN INCREASE PLASMA DIGOXIN LEVELS

Fibric Acid Derivate (Fibrate) Weight loss medication that is inhibitor of gastric & pancreatic Activates PPARα size of LDL particles, removal of LDL, lipases in stomach & small intestine TG absorbed 30% Weight loss in obese pts serum cholesterol, risk factors & co- levels of plasminogen activator inhibitor type 1, Apo AI & Apo AII morbidities such as Type 2 DM, impaired glucose tolerance, ( HDL), Apo CIII ( lipoprotein lipase) & Enhances hyperinsulinemia, hypercholesterolemia, & HTN oxidation of FA in liver & muscle and reduce lipogenesis in liver Adverse effects: Oily spotting, flatus w/ discharge, fecal urgency, hepatic secretion of VLDL = LDL 5-20%, HDL 10-35%, fatty/oily stool, oily evacuation, defecation & fecal incontinence ( TG 20-50% if fat of diet >30%), i vit ADEK & β-carotene Rx: hyperTG (1º use ) & atherogenic dyslipidemia CI: chronic malabsorption syn, cholestasis, or allergic Adverse effects: Dyspepsia, chol gallstones, myopathy DI: possibly need to change dose of warfarin (b/c i vit K) & oral CI: severe hepatic or renal insufficiency, gallbladder dz hypoglycemics, cyclosporine levels May enhance action of warfarin

Bile Acid Sequestrant –“+” charged anion exchange resins Competitive inhibitor of HMG CoA reductase Not absorbed in GI tract but binds bile acids & bile acid excretion; liver cholesterol syn liver LDL receptor syn plasma LDL Cl cholesterol absorp liver chole. syn ( HMG CoA reductase) = LDL 18-55%, HDL 5-15%, TG 7-30% plasma TG; LDL catabolism/Cl ( LDL receptor syn) = Reduces risk for CHD & stroke LDL, HDL, no change TG Adverse effects: Myopathy, AST& ALT (both dose-related Adverse effects: Upper & lower GI complaints; absorption of Absolute CI: active or chronic liver dz, pregnancy other drugs (warfarin, digoxin, thiazide diuretics, statins, vitamins Relative CI: Concomitant use of cyclosporine, macrolide A,D, E, K) (take drugs 1h before or 4h after resin) antibiotics, various anti-fungal agents, & CP450 inhibitors (fibrates Absolute CI: Familial dysbetalipoproteinemia & TG >400mg/dL; & nicotinic acid use w/ appropriate caution) Relative CI: TG >200 mg/dL Can use w/ resins or ezetimibe Can use w/ statins (but risk of rhabdomyolysis)

Fibric Acid Derivate (Fibrate) (not used due to gallstones) Competitive inhibitor of HMG CoA reductase Activates PPARα size of LDL particles, removal of LDL, liver cholesterol syn liver LDL receptor syn plasma LDL Cl levels of plasminogen activator inhibitor type 1, Apo AI & Apo AII = LDL 18-55%, HDL 5-15%, TG 7-30% ( HDL), Apo CIII ( lipoprotein lipase) & Enhances Reduces risk for CHD & stroke oxidation of FA in liver & muscle and reduce lipogenesis in liver Adverse effects: Myopathy, AST& ALT (both dose-related hepatic secretion of VLDL = LDL 5-20%, HDL 10-35%, Absolute CI: active or chronic liver dz, pregnancy TG 20-50% Relative CI: Concomitant use of cyclosporine, various anti-fungal Rx: hyperTG (1º use ) & atherogenic dyslipidemia agents, & CP450 inhibitors (fibrates & nicotinic acid use w/ Adverse effects: Dyspepsia, chol gallstones, myopathy appropriate caution) CI: severe hepatic or renal insufficiency, gallbladder dz Can use w/ resins or ezetimibe May enhance action of warfarin

Rosuvastatin Gemfibrozil (Crestor (Lopid)

)

Colesevelam Lovastatin (Welchol )

(Mevacor)

Simvastatin

Colestipol

(Zoc or)

(Colestid )

Nicotinic acid Omega-3 PUFA

(Niaci n)

(Lovaza – formerly Omacor)

Vytorin (Ezetimibe/Simvastatin)

Ezetimibe

(Zetia)

Fibric Acid Derivate (Fibrate) Competitive inhibitor of HMG CoA reductase Activates PPARα size of LDL particles, removal of LDL, liver cholesterol syn liver LDL receptor syn plasma LDL Cl levels of plasminogen activator inhibitor type 1, Apo AI & Apo AII = LDL 18-55%, HDL 5-15%, TG 7-30% ( HDL), Apo CIII ( lipoprotein lipase) & Enhances Reduces risk for CHD & stroke oxidation of FA in liver & muscle and reduce lipogenesis in liver Adverse effects: Myopathy, AST& ALT (both dose-related hepatic secretion of VLDL = LDL 5-20%, HDL 10-35%, Absolute CI: active or chronic liver dz, pregnancy TG 20-50% Relative CI: Concomitant use of cyclosporine, macrolide antibiotics, Rx: hyperTG (1º use ) & atherogenic dyslipidemia various anti-fungal agents, & CP450 inhibitors (fibrates & nicotinic Adverse effects: Dyspepsia, chol gallstones, myopathy acid use w/ appropriate caution) CI: severe hepatic or renal insufficiency, gallbladder dz Can use w/ resins or ezetimibe May enhance action of warfarin

Bile Acid Sequestrant - Polymeric hydrophilic gel Competitive inhibitor of HMG CoA reductase Not absorbed in GI tract but binds bile acids & bile acid excretion; liver cholesterol syn liver LDL receptor syn plasma LDL Cl cholesterol absorp liver chole. syn ( HMG CoA reductase) = LDL 18-55%, HDL 5-15%, TG 7-30% plasma TG; LDL catabolism/Cl ( LDL receptor syn) = Reduces risk for CHD & stroke LDL, HDL, no change TG Adverse effects: Myopathy, AST& ALT (both dose-related Adverse effects: Upper & lower GI complaints; absorption of Absolute CI: active or chronic liver dz, pregnancy other drugs (warfarin, digoxin, thiazide diuretics, statins, vitamins Relative CI: Concomitant use of cyclosporine, macrolide antibiotics, A,D, E, K) (take drugs 1h before or 4h after resin) various anti-fungal agents, & CP450 inhibitors (fibrates & nicotinic Absolute CI: Familial dysbetalipoproteinemia & TG >400mg/dL; acid use w/ appropriate caution) Relative CI: TG >200 mg/dL Can use w/ resins or ezetimibe Can use w/ statins (but risk of rhabdomyolysis)

Bile Acid Sequestrant – “+” charged anion exchange resins Competitive inhibitor of HMG CoA reductase Not absorbed in GI tract but binds bile acids & bile acid excretion; liver cholesterol syn liver LDL receptor syn plasma LDL Cl cholesterol absorp liver chole. syn ( HMG CoA reductase) = LDL 18-55%, HDL 5-15%, TG 7-30% plasma TG; LDL catabolism/Cl ( LDL receptor syn) = Reduces risk for CHD & stroke LDL, HDL, no change TG Adverse effects: Myopathy, AST& ALT (both dose-related Adverse effects: Upper & lower GI complaints; absorption of Absolute CI: active or chronic liver dz, pregnancy other drugs (warfarin, digoxin, thiazide diuretics, statins, vitamins Relative CI: Concomitant use of cyclosporine, macrolide antibiotics, A,D, E, K) (take drugs 1h before or 4h after resin) various anti-fungal agents, & CP450 inhibitors (fibrates & nicotinic Absolute CI: Familial dysbetalipoproteinemia & TG >400mg/dL; acid use w/ appropriate caution) Relative CI: TG >200 mg/dL Can use w/ resins or ezetimibe Can use w/ statins (but risk of rhabdomyolysis)

Antidyslipidemic drug (Useful most lipid & lipoprotein abnl) EPA & DHA (PUFAs) lipolysis by adenylyl cyclase activity FFA levels VLDL syn of TG & VLDL; LDL but size changes larger, more buoyant particles (less atherogenic); minimal effects on HDL syn TAG &VLDL LDL; HDL; Lp(a); arachidonic acid 4g/qday or 2gBID w/ meals = TG 20-50% & VLDL 30-40%; cascade (Langerhans cells) PGD2 flushing = LDL 5-25%, HDL 6-13% & LDL 15-30%; low doses (1g/day) which has modest HDL 15-35%, TG 20-50% effect on TG, reduces coronary heart dz & mortality (prob due to Absolute CI: Chronic liver dz, severe gout; Relative CI: inhibition of platelet aggregation) hyperuricemia & high doses in Type 2 DM Adjunct to diet for rx of very high TG (>500mg/dL) Adverse effects: hepatotoxicity (esp w/ crystalline & sustained/time Adverse effects: belching, dyspepsia, taste perversion, glycemic release), hyperglycemia, hyperuricemia/gout, worsens peptic ulcer control in diabetics, impaired hemostasis dz. risk of rhabdomyolysis w/ statins Does not risk of rhabdomyolysis when comb w/ statins Need 1-3 g /day (Vit dose 20mg/day) Max 2-4.5g/day

Cholesterol Absorption Blocker Inhibits absor of cholesterol & related phytosterols intestinal cholesterol stores Cl cholesterol = Alone: Fixed dose-dose combination of ezetimibe 10mg and simvastatin cholesterol to liver (10, 20, 40, or 80 mg) Total-Cl ~13%, LDL 18%, Apo B 16%, TG 8% & HDL 1%. w/ statin: Total-Chol 17%, LDL 25%, Apo B 19%, TG 14%, & Decreases LDL greater than can be achieved by doubling the statin HDL 3% dose if only a statin is used Rx: 1º & homo familial hypercholesterolemia, homo sitosterolemia (phytosterolemia) (only med approved) Increased risk of rhabdomyolysis Adverse Effects: myalgia-Rhabdomyolysis, diarrhea, h liver enzymes esp when used w/ statins CI: liver dz; DI: Fibrates bioavail & cholestyramine

Adivor (Niaspan + Lovastatin) (Not in notes, but was in ppt)

Simcor (Niaspan + Simvastatin) (Not in notes, but was in ppt)

Bile acid sequestrants (AKA resins)

HMG CoA Reductase Inhibitor

Cholesterol Absorption Blocker

Fibric Acid Derivates (Fibrates)

Iron

Vitamin B12

Folic Acid

Erythropoietin

Extended release Nicotinic acid plus lovastatin

Extended release Nicotinic acid plus simvastatin

Increased risk of rhabdomyolysis

Increased risk of rhabdomyolysis

Decreases LDL, Increases HDL, Decreases TG Increases # LDL receptors Decreases cholesterol synthesis Increase risk of rhabdomyolysis (rare) Ex) Lovastatin, Pravastatin, Fluvastatin, Simvastatin, Atorvastatin, Rosuvastatin

Decreases LDL (in hyperTG, may raise LDL), Increass HDL, Decreases TG Decreases Apo CIII (reduces inhibition of lipoprotein lipase (LPL)) Increases Apo AI & Apo AII Increases oxidation of Fatty acids Decreases lipogenesis Decreases VLDL secretion

Decreases LDL, Increases HDL minimally, no change in TG Increases Bile acid excretion Decreases dietary cholesterol absorption Increases # LDL receptors Ex) Cholestyramine, colestipol, colesevelam

Decreases Total Cholesterol, Decreases LDL, Decreases Apo B, Decreases TG, Increases HDL Decreases dietary cholesterol & related phytosterols absorption Ex) Ezetimibe

Ex) Fenofibrate, Gemfibrozil, Clofibrate

Best absorbed in ferric form in the duodenum & prox jejunum (distal Cofactor for several essential biochemical rxn sm intestine can absorb if necess); amt absorbed depends on need: Deficiency leads to megaloblastic (B12 def) or pernicious anemia pregnant > nl menstruating women> post-menopausal & males (B12 due to intrinsic factor def), GI symptoms, & neuro Iron storage controlled by absorption & serum ferritin levels abnormalities; Takes abt 5 yrs for store to be depleted Causes: IF def, partial or total gastrectomy, malabsorption syn, estimate iron stores; Serum transferrin in iron deficiency inflammatory bowel dz or sm bowel resection 200-400mg elemental iron/day for 3-6 mths after correction to Parenteral or IM of B12 (hydroxocobalamin (preferred) or replenish stores; Parenteral therapy: iron dextran (IM or iv), ironcyanocobalamin) daily or every other day every 1-2 wks to replace sucrose complex (iv), iron sodium gluconate complex (iv) Toxicity: Whole bowel irrigation & deferoxamine (iron chelator) for stores. Maintenance 100-1000mcg IM once a mth. High dose of oral B12 if pt refuses or can’t do shots acute; intermittent phlebotomy for chronic

Hematopoietic growth factor w/ ½ life of 4-13 Used in pts w/ anemia of chronic renal failure, primary bone marrow Reduced form required for rxns that provide precursors for syn of disorders (aplastic anemia, myeloproliferative & myelodysplastic amino acids, purines, & DNA dz, multiple myeloma) & secondary anemias (chronic inflammation, Body stores are relatively low & daily requirements are high def & AIDS, cancer & anemia from zidovudine treatment in HIV pts & megaloblastic anemia can occur w/in 1-6mths (RBC levels of folate anemia of prematurity) more dx value than serum) Normally, except in renal dz (b/c kidneys can’t make it), as Deficiency often b/c poor diet, but also caused by methotrexate, hematocrit & Hb falls, serum EPO rises exponentially b/c it trimethoprim, pyrimethamine, phenytoin & other anticonvulsants erythroid proliferation & differentiation (won’t cause megaloblastic anemia usually). No neuro symptoms. Failure to respond = concurrent iron def Oral folate supplements (1mg/day) until def cause fixed Toxicity = HTN & thrombotic complications

Darbepoetin alfa

Pegfilgrastim

Sargramostim (rHuGM-CSF)

Filgrastim (rHuG-CSF)

Oprelvekin

Thrombopoietin

Myeloid Growth Factor – covalent conjugation product of filgrastim & a form of polyethylene glycol Longer ½ life of filgrastim Injected once per myelosuppressive chemotherapy cycle

Glycosylated form of erythropoietin Functionally the same as erythropoietin except it has a twofold to threefold longer half-life

Myeloid Growth Factor w/ ½ life 2-7 hrs after iv or SQ Myeloid Growth Factor w/ ½ life 2-7 hrs after iv or SQ Injected daily for several days for each chemotherapy cycle Multipotential hematopoietic growth factor that proliferation & differentiation of early & late granulocytic progenitor cells and prolife & differentiation of progenitors already committed to neutrophil lineage; phagocytic activity of mature neutrophils & erythroid & megakaryocyte progenitors; fxn of mature neutrophils; prolongs their survival; mobilizes hematopoietic stem cells acts w/ IL-2 to T-cell proliferation; mobilizes peripheral blood For: peripheral blood stem cell transplantation, cyclic neutropenia, stem cells (but not as well as G-CSF) cancer chemotherapy-induced neutropenia (inc. acute myeloid For: cyclic neutropenia, cancer chemotherapy-induced neutropenia leukemia), congenital neutropenia, myelodysplasia, & aplastic (inc. acute myeloid leukemia), congenital neutropenia, anemia myelodysplasia, & aplastic anemia Toxicity: well tolerated – may cause bone pain but clears when drug Toxicity: fever, malaise, arthralgias, myalgias, cap leak syn, splenic is stopped rupture (rare)

Used in pts w/ thrombocytopenia, 2º prevention in pts getting cytotoxic chemo for nonmyeloid cancers Still an investigational agent, but so far well tolerated Recombinant form of IL-11 w/ ½ life of 7-8 hrs Stimulates growth of multiple lymphoid & myeloid cells; acts Low in pts w/ cirrhosis (b/c it is made in the liver normally) & synergistically w/ other growth factors to growth of primitive thrombocytopenia (w/out anemia or leukopenia if no other growth megakaryocytic progenitors & number of peripheral platelets & factor is missing) neutrophils Stimulates growth of primitive megakaryocytic progenitors; 50mcg/kg/day SQ 6-24 hrs after completion of chemo & continued stimulates mature megakaryocytes & even activates mature platelets for 14-21 dys or until platelet # >50,000/µL to respond to aggregation-inducing stimuli Adverse effects: fatigue, headache, dizziness, anemia, dyspnea, transient atrial arrhythmias, hypokalemia