MENNONITE COLLEGE OF NURSING

AT

ILLINOIS STATE UNIVERSITY

Pharmacotherapeutics for Advanced Practice Nursing 433

 

Drugs Used to Treat Diseases of the Blood

 

Hyperlipoproteinemic (Antilipemic) Agents

 

A brief pathophysiology review:

·         Two primary forms of lipids are triglycerides and cholesterol

·         Triglycerides function as an energy source and are stored in adipose (fat) tissue

·         Cholesterol is primarily used to make steroid hormones, cell membranes, and bile acids

·         Lipoproteins transport lipids via the blood

·         HDL = high density lipoprotein (“good” cholesterol)

·         LDL = low density lipoprotein (“bad” cholesterol)

·         VLDL = very low density lipoprotein

 

 

Lipoprotein Classification:

 

Most ß---------------------------------- Lipid content ---------------------------------------------à Least

 

Chylomicron              VLDL          LDL                        Intermediate-density                     HDL

 

Least ß---------------------------------- Protein content -------------------------------------------à Most

 

 

 

Link between cholesterol and CHD

·         Lipids and lipoproteins participate in the formation of atherosclerotic plaques, which leads to CHD

·         Lipids or plaque form in the blood vessels that supply the heart with needed oxygen and nutrients

·         They eventually decrease the lumen size of these blood vessels, thus reducing the amount of oxygen that can reach the heart

 

 

Types of Hyperlipidemias:

 

Phenotype

Lipid Composition

Cholesterol

Triglyceride

IIa

Elevated

Normal

IIb and III

Elevated

Elevated (1-3 X higher than cholesterol)

IV

Normal or mildly elevated

Elevated

I and V

Elevated (> 300 mg/dl)

Elevated (> 1000 mg/dl)

 

 

 

Good goals for individuals with no risk factors:

·         Total cholesterol (TC) < 200 mg/dl

·         HDL > 60 mg/dl

·         LDL < 130 mg/dl

·         Total cholesterol/HDL < 5.0 is desirable


Risk Factors for High Blood Cholesterol

Positive Risk Factors

·         Age

·         Male >/= 45 years

·         Female >/= 55 or women with premature menopause not on estrogen replacement therapy

·         Family history

·         History of premature CHD (e.g., MI or sudden death before 55 years of age in father or other male first-degree relative, or before 65 years of age in mother or other female first-degree relative.)

·         Current cigarette smoker

·         Hypertension: >/= 140/90 mm Hg., or on antihypertensive medication

·         Low HDL cholesterol level: <35 mg/dl

·         Diabetes mellitus

 

Negative Risk Factors

·         High HDL cholesterol:  >/= 60 mg/dl – if the HDL cholesterol is >/= 60 mg/dl, subtract one risk factor.

 

 

The decision to prescribe hyperlipemic drugs as an adjunct to diet therapy in patients with an elevated cholesterol level should be based on the patient’s clinical profile (age, sex, menopausal status, family history, response to dietary treatment, presence of risk factors, and course/duration/phenotypic pattern of patient’s hyperlipidemia.

 

The National Cholesterol Education Program (NCEP) guidelines recommend all patients with LDL > 190 mg/dl and those with LDL 160-190 who have CHD or 2 or more risk factors be considered for drug therapy after an adequate trial (6 months) of dietary and other nondrug therapies have proved ineffective.

 

Antilipemics (= antihyperlipidemics):  drugs used to lower high levels of lipid (triglycerides and cholesterol)

 

Major classes of antilipemics:

·         Bile acid sequestrants

·         Fibric acid derivatives

·         Nicotinic acids

·         HMG-CoA reductase inhibitors

 

 

Bile acid sequestrants (=bile-acid binding resins = ion exchange resins)

·         Decrease LDL 15-30%

·         Increase HDL 3-8%

·         Increase hepatic triglyceride and VLDL production à 10-50% increase in triglycerides

·         Used for type IIa hyperlipidemia

·         Mechanism of action:  bind with bileà prevent the resorption of the bile acids from the small intestine à depletion of bile acid pool à stimulates hepatic synthesis of bile acids from cholesterol à decreased pool of cholesterol in liver à increased cholesterol biosynthesis and the # of high-affinity LDL receptors expressed on the liver’s surface à increased rate of LDL catabolism à increased removal of LDL from bloodstream à decreased plasma LDL levels.

·         The result of the ion-exchange resin binding to the bile acids is an insoluble resin-bile acid complex that is excreted by means of the feces.

·         Note:  High doses of bile acid sequestrants decrease absorption of fat-soluble vitamins (A, D, E, K)

·         Examples:  cholestyramine (Questran), colestipol hydrochloride (Colestid)

·         Adverse effects:  constipation, heartburn, nausea, belching, bloating, bleeding, headache, tinnitus, burnt odor to urine

·         GI effects decrease with time

·         Contraindications:  complete biliary obstruction (although, Questran has been used to relieve pruritus associated with partial biliary obstruction)

·         Prescribing: 

·         Initiate therapy in low doses

·         Instruct to take with meals to decrease side effects

·         Other drugs should be taken at least 1 hour before or 4-6 hours after the ion-exchange resin

 

 

Fibric Acid Derivatives (= fibrates)

·         Decrease triglyceride levels

·         Increase HDL by up to 25%

·         Decrease LDL in IIa and IIb, but increase LDL in type IV and V hyperlipidemia

·         Used for treatment of type III, IV, V and in some cases, IIb hyperlipidemia

·         Mechanism of action:  inhibits peripheral lipolysis and decreases the hepatic excretion of free fatty, acids; this reduces hepatic triglyceride production, decreases VLDL production, increases HDL concentration

·         Examples:  gemfibrozil (Lopid), fenofibrate (Tricor)

·         Adverse effects: 

·         GI:  N, V, diarrhea, gallstones, acute appendicitis

·         GU:  impotence, decreased urine output, hematuria, increased risk of UTIs and viral infections

·         Hematologic:  agranulocytosis (rare), thrombocytopenia (rare), elevated LFTs

·         Other:  drowsiness, dizziness, rash, pruritus, alopecia, eczema, vertigo, headache, prolonged prothrombin time

·         Gemfibrozil (generic, Lopid)  

·         Decreases VLDL, increases HDL

·         Very effective at decreasing triglycerides

·         Used for type IV, V, and some IIb

·         Fenofibrate (Tricor)

·         Decreases triglycerides

·         Renal dosing; contraindicated if CrCl < 20

 

Nicotinic acid (= Niacin = vitamin B3)

·         Inhibits synthesis of VLDL and LDL in the liver by 10-15% and increases HDL

·         Decreases triglycerides 20-80%

·         Used in types IIa, IIb, III, IV, V

·         To decrease lipids, much larger doses of the agent are required than are commonly given when used as a vitamin

·         Effects begin in 1-4 days; maximum seen after 3-5 weeks of continuous therapy

·         Adverse effects (* Minimize by starting with low initial dosage and increase slowly)

·         Skin:  cutaneous flushing (vasodilation), pruritus, hyperpigmentation

·         Administer at bedtime to minimize flushing

·         ASA 30 minutes before niacin also decreases flushing

·         GI:  abdominal discomfort, GI distress

·         Other:  blurred vision, glucose intolerance, hyperuricemia, rarely dry eyes, hepatotoxicity

·         Take with meals (usually bid – tid)

·         A sustained release niacin is available as Niaspan, which is taken at hs

·         Niacin potentiates hypotensive effects of ganglionic blockers (used in HTN crisis

·         Niacin + HMG-CoA reductase inhibitors = risk of myopathy occurring (rhabdomyolysis)

·         Increased risk of bleeding with anticoagulants


 

HMG-CoA reductase inhibitors (HMG = hydroxymethylglutaryl)

·         Decrease LDL 30-40%

·         Decrease triglycerides 10-30%

·         Increase HDL 2-15%

·         Used for types IIa and IIb hyperlipidemia

·         Mechanism of action:  The liver requires HMG-CoA reductase to produce cholesterol.  The “statins” inhibit HMG-CoA reductase à decreased cholesterol production à liver has increased # of LDL receptors.

·         Adverse effects:

·         GI:  constipation, cramps, diarrhea, nausea, changes in bowel function

·         CNS:  headache, dizziness, blurred vision, fatigue, insomnia, asthenia (lack or loss of strength), ophthalmoplegia (paralysis of ocular muscles)

·         Other:  myalgias, skin rashes, increased liver enzymes

·         Well-tolerated:  side effects uncommon

·         Use cautiously with oral anticoagulants

·         Coadministration with erythromycin, gemfibrozil, or niacin à development of rhabdomyolysis (rare)

 

Very little difference in clinical effects of the “statin” drugs

 

 

Atorvastatin

(Lipitor)

Rosuva-statin (Crestor)

Fluvastatin

(Lescol)

Lovastatin

(Mevacor)

Pravastatin

(Pravachol)

Simvastatin

(Zocor)

Dose (mg)

10-80

5-40

20-80

20-80

10-80

10-80

% HDL increased

5

7.7-10%

5-8

6-9.5

7-12

7-12

% TG reduced

19-37

23%

10-11

10-19

15-24

26-48

% Apo – B reduced

32-50

 

14-26

21-34

16-37

19-47

% LDL reduced

35-60

45-55%

20-30

25-40

22-34

25-40

Cost /mo ($)

$64.99-94.99

$69.99-80.90

$53.99

$40.99-122.99

$82.99-124.99

$69.99-123.99

 

Adapted from:  June 15, 1993 issue of Drug Topics; updated January 2004.

 

ezetimibe (Zetia)

  • First in new class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols
  • Localizes and appears to act at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver

This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of HMG-CoA reductase inhibitors

  • Suggested dosing: 
    • The patient should be placed on a standard cholesterol-lowering diet before receiving Zetia and should continue on this diet during treatment with Zetia.
    • The recommended dose is 10 mg once daily; can be administered with or without food
    • May be administered with an HMG-CoA reductase inhibitor for incremental effect and may be taken at the same time as the HMG-CoA reductase inhibitor.
    • Dosing of Zetia should occur either ≥ 2 hours before or ≥4 hours after administration of a bile acid sequestrant
    • No dosage adjustment is necessary in patients with mild hepatic insufficiency, in patients with renal insufficiency, or in geriatric patients
  • In the “Add-on” study, adding Zetia to ongoing statin treatment provided a 25% (36 mg/dL) additional reduction in LDL cholesterol vs. 4% (6 mg/dL) with the addition of placebo
  • Liver function tests are not required when Zetia is used alone.
  • In clinical trials, there was no increased incidence of myopathy or rhabdomyolysis associated with Zetia
  • Safety and effectiveness of Zetia with fibrates have not been established; therefore, coadministration with fibrates is not recommended.
  • Cost:  $71.99/month

 

Selecting a Cholesterol-lowering Agent

The choice of a cholesterol-lowering agent is based on patient-specific treatment goals, the drug’s efficacy and safety profile, and cost and compliance considerations.

 

Class

Generic/

Product Name

Dosing

(How Supplied)

Action

Side Effects

Absolute Contraindications

Bile Acid Sequestrants

Cholestyramine

Questran Powder

 

Colestipol

Colestid (granules, tablets)

4-24 gm/day

 

5-30 gm/day for granules,

2-16 gm/day for tablets

Decrease LDL

+/- HDL

Increase TG

Decrease TC

Constipation, N, bloating.  May cause decreased absorption of fat-soluble vitamins and other drugs. Increased bleeding tendencies

Diverticulitis

Active ulcer disease

Chronic constipation

Complete biliary obstruction

Nicotinic Acid

Nicotinic Acid

 

 

Niaspan

500-5000 mg/day

 

375-1,000 mg ER tabs

Decrease LDL

Decrease TG

Increase HDL

Decrease TC

Flushing, pruritus/dry skin, GI discomfort/ GI irritation, Elevated liver enzymes, hyperglycemia, hyperuricemia

Active peptic ulcer disease/active liver disease

Gout (relative)

Diabetes mellitus (relative)

Intermittent atrial fib (relative)

Pregnancy

Fibrates

Gemfibrozil

Lopid

 

Fenofibrate

Tricor

1200 mg/day

 

48-160 mg/day

Decrease TG

Increase HDL

Decrease/ increase LDL

Decrease TC

Dyspepsia, N, V, abdominal and epigastric pain, rash, Attenuates anticoagulants

Cholelithiasis

Myositis

Myopathy

Rhabdomyolysis (rare)

Elevated LFTs

Acute liver disease

Severe renal disease

Gallbladder disease

Immunosuppressed patients

Primary biliary cirrhosis

Pregnancy

Persistent abnormal LFTs

 

HMG-CoA Reductase Inhibitors

See table on previous page

See table on previous page

Decrease LDL

Increase HDL

Decrease TC

Decrease TG

GI disorders, Headache

Interaction with gemfibrozil, Tricor, niacin and immuno- suppressive drugs.

Elevated LFTs

Dyspepsia, flatus, muscular/joint discomfort

Active liver disease

Pregnancy

Other

ezetimibe (Zetia)

10 mg

Decrease LDL primarily, some improvement in TG and HDL

Mild; fatigue, diarrhea, sinusitis, arthralgia

Active liver disease, unexplained elevated LFTs, pregnancy, nursing women

 

 

Combination Therapy

 

As a rule, combination therapy with statins and resins or statins, resins, and niacin is considered when the lipid abnormality is severe and therapy with a single agent does not achieve goal levels.

 

It is also used when lower doses of 2 or more drugs will avoid the toxicity seen with higher doses of a single drug.

 

Moreover, since statins tend to have less incremental benefit as the dosage is doubled and redoubled, adding a drug with a complementary mode of action, such as a resin, may be more cost-effective than simply increasing the statin dosage.

 

At lower levels of LDL cholesterol, unmodified niacin and resin can be very cost-effective. 

 

At higher levels of LDL cholesterol, statin and resin therapy is usually required to reach goal levels.

 

Zetia can be used in combination with statins and bile acid sequestrants.  There is a combination drug now available:  Vytorin, which is ezetimibe (Zetia) plus simvastatin (Zocor) .  Available doses include 10/10, 10/20, 10/40, and 10/80.

 

Another combination:

  • Advicor = lovastatin (Mevacor) 20 mg + Niacin 500 mg
    • Take a regular strength ASA ½ hour before Advicor to prevent flushing

 

Older Patients

The NCEP report recommends that health care providers use their clinical judgment when considering cholesterol-lowering therapy for older patients.  Findings from the 4S (Scandinavian Simvastatin Survival Study) suggest that patients aged 60-70 at entry derived as much benefit from treatment as did those who were younger.  Thus, for those > 70 years with CAD but in otherwise good health, treatment to reduce LDL cholesterol should be strongly considered.  On the other hand, for healthy patients in this age group who are without significant risk of CAD, or for those with serious comorbidity, a more conservative approach is indicated.

 

Don’t Forget…

…the importance of diet (medication is NOT in place of dietary changes)

 


Antithrombotic Therapy

 

 

Available antiplatelet meds:

 

  • Aspirin
    • 81 mg. for post-MI, patients with CAD
    • Study:  “Aspirin is just as effective as warfarin at preventing recurrent ischemic stroke in patients without atrial fibrillation.  It’s also safer, cheaper, and easier to use.”  (Study reported by Mohr, et al, in New England Journal of Medicine, 2001)
    • Study reported in Journal of the American College of Cardiology (March 17, 2004):  Prolonged treatment with aspirin is associated with a progressive reduction in antiplatelet activity (after 2 years of treatment), but the same is not true for prolonged treatment with ticlopidine (Ticlid). 
    • Other researchers have observed a reduction in cardiovascular events when treatment with aspirin was combined with clopidogrel (Plavix), another antiplatelet agent.
  • Ticlopidine (Ticlid)
  • Clopidogrel (Plavix)
  • Dipyridamolde (=Persantine) + aspirin  = Aggrenox
  • Cilostazol (Pletal)—used for intermittent claudication
    • Contraindicated in patients with congestive heart failure of any severity
      • Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III.  Several drugs with this pharmacological effect have caused decreased survival compared with placebo in patients with class III-IV CHF.

 

Available anticoagulant meds:

 

  • Warfarin (Coumadin) 
    • Warning from the British Committee on Safety of Medicines that patients taking warfarin should limit or avoid drinking cranberry juice because of the risk of hemorrhage.
    • Monitor with PT/INR
  • Heparin
    • Caution re:  Heparin-induced thrombocytopenia (HIT) and resulting thrombosis
    • Monitor with PTT
  • Enoxaparin (Lovenox)
    • HIT can occur with Lovenox…if platelet count falls below 100,000/mm3, discontinue Lovenox

New info on Pradexa, etc.  will be provide in class!

 

 

 

The Seventh ACCP (American College of Chest Physicians) Conference on Antithrombotic and Thrombolytic Therapy:  Evidence-Based Guidelines:

 

http://www.chestjournal.org/content/vol126/3_suppl/

 

Guide can be purchased by phone order only: (800) 343-2227 or 847-498-1400 (www.chestnet.org)

 

 

Major research findings from the past conferences: 

·         Low doses of aspirin (80-325 mg) are as effective as higher doses (500-1,000 mg) in cerebrovascular disease.

·         The oral antiplatelet agent clopidogrel (Plavix) and the intravenous glycoprotein IIb-IIIa antagonists are confirmed as important antithrombotic agents.

·         Oral GPIIb/IIIa antagonists have not been found effective in myocardial ischemia.

·         Like aspirin and ticlopidine (Ticlid), aspirin and clopidogrel (Plavix) have a synergistic effect in patients with coronary stents.

·         Low-molecular-weight heparin (LMWH) is an effective replacement for unfractionated heparin (UFH) in acute coronary ischemic syndromes and in venous thromboembolism (VTE).

·         The lower limit of the therapeutic range for oral anticoagulants in atrial fibrillation (AF) is an international normalized ration (INR) of 2.0.

·         Combining low-intensity warfarin (either fixed low-dose, or INR < 2.0) with aspirin has not been proven beneficial in patients with AF.

 

 

 

Remember: 

·         warfarin (Coumadin), heparin, and antiplatelet agents prevent clot formation, but they do not lyse preformed clots

·         thrombolytics DO break down or lyse preformed clots

 

 

 

Coronary Artery Disease

·         For long-term therapy, aspirin offered if embolic risk is low, warfarin if it is high.

·         If aspirin is contraindicated, Plavix 75 mg/day given indefinitely

·         Warfarin (goal INR 2.5, range 2.0-3.0) is an alternative, but involves increased complexity, risk, and cost

 

Primary Prevention of CAD:

They Do NOT recommend routine use of aspirin in patients < 50 years of age, with no history of AMI, stroke, or TIA.

 

They DO recommend:

·         Patients > 50 years of age, with at least one major risk factor for CAD (cigarette smoking, HTN, DM, high cholesterol levels, parental history of infarction) be offered aspirin therapy, in the absence of contraindications, along with aggressive BP control (goal = diastolic pressure < 85 mm Hg)

 

 

Use of Oral Anticoagulants

 

Indication

INR Range

·         Prophylaxis of venous thrombosis (high-risk surgery)

·         Treatment of venous thrombosis

·         Treatment of PE

·         Prevention of systemic embolism

·         Tissue heart valves

·         AMI (to prevent system embolism)

·         Valvular heart disease

·         AF

2.0 to 3.0

Mechanical prosthetic valves (high risk)

2.5 to 3.5

Bileaflet mechanical valve in aortic position

2.0 to 3.0

Certain patients with thrombosis and the antiphospholipid syndrome

> 2.0 to 3.0

 


Managing Oral Anticoagulant Therapy

 

They recommend starting warfarin therapy with an average maintenance dose of 5 mg, which usually is sufficient to lower the INR to 2.0 in 4 or 5 days.  Lower starting doses may be appropriate in elderly patients, those with liver disease or inadequate nutrition, and those at high risk for bleeding.  Larger starting doses, e.g. 7.6 to 10 mg, may be selected if a rapid effect is urgently needed.  A loading dose of warfarin is unnecessary for most patients.

 

Heparin can be given concurrently for 4 or more days if a rapid effect is required.  Heparin therapy is usually discontinued when the INR has been within therapeutic range in two measurements taken 24 hours or more apart.

 

Managing Patients With High INR Values

 

Clinical Situation

Guidelines

INR > therapeutic range but < 5.0; no significant bleeding

Lower the dose; or omit the next dose, and resume therapy at a lower dose when the INR is within therapeutic range; if the INR is only slightly above therapeutic range, dose reduction may not be necessary.

INR > 5.0, but < 9.0; no significant bleeding

Omit the next dose or two, monitor INR more frequently, and resume therapy at a lower dose when the INR is within therapeutic range.

 

Alternatively, omit a dose and give vitamin K (1-2.5 mg orally), especially if the patient is at increased risk for bleeding.

 

Patients requiring more rapid reversal before urgent surgery:  vitamin K (2-4 mg orally); if INR remains high at 24 h:  an additional dose of vitamin K (1-2 mg orally)

INR > 9.0; no significant bleeding

Omit warfarin; give vitamin K (3-5 mg orally); closely monitor the INR; if the INR is not substantially reduced in 24-48 hours, monitor the INR more often, giving additional vitamin K, if necessary

INR > 20; serious bleeding

Omit warfarin; give vitamin K (10 mg, slow IV infusion), supplemented with fresh plasma or prothrombin complex concentrate, depending on urgency; vitamin K injections can be repeated every 12 hours.

Life-threatening bleeding

Omit warfarin; give prothrombin complex concentrate with vitamin K (10 mg by slow IV infusion); repeat if necessary, depending on the INR.

 


Hematopoietic Drugs

 

Folic acid

·         Water-soluble vitamin B-complex

·         Used for normal erythropoiesis and to produce nucleoproteins such as DNA and RNA

·         Important for closure of neural tube in fetal development

 

 

Iron Preparations

·         Oral iron salts or parenteral iron salt (iron dextran)

·         Ferrous salts vary in their iron content

·         Ferrous fumarate (Femiron) = 33% iron or 330 mg/g

·         Ferrous gluconate = 12% iron or 120 mg/g

·         Ferrous sulfate = 20% iron or 200 mg/g

·         Ferrous sulfate (dried) = 30% iron or 300 mg/g

·         Adverse effects

·         GI:  nausea, constipation, epigastric pain, black and red tarry stools, vomiting, diarrhea

·         Integumentary:  temporarily discolored tooth enamel and eyes, pain upon injection

·         Patient should avoid reclining position for 15-30 minutes after taking the drug to avoid esophageal irritation or corrosion.

·         Drug Interactions

·         Antacids à decreased iron absorption

·         Quinolone antibiotics à decreased quinolone absorption

·         Tetracyclines à decreased tetracycline absorption

·         Thyroid drugs à decreased thyroid absorption

·         Ascorbic acid à increased iron absorption ***

·         Note:  Iron is not eliminated physiologically by the body and therefore excess iron intake can lead to accumulation and iron toxicity.

 
 
Vitamin B12 (= cyanocobalamin)

·         Water-soluble B complex vitamin

·         The oral absorption of cyanocobalamin requires the presence of the intrinsic factor secreted by gastric parietal cells.

·         If no intrinsic factor, must give IM

·         Adverse effects (with LARGE doses):

·         CNS:  flushing, optic nerve atrophy

·         Integumentary:  itching, rash, pain at injection site

·         CV:  CHF, PV thrombosis, pulmonary edema

·         GI:  diarrhea

·         Metabolic:  hypokalemia

·         Interactions:  anticonvulsants, aminoglycosides, and long-acting K+ preps, decrease the oral absorption of vitamin B12.