Post on 23-Dec-2015
Hypertension
• Hypertension common in US, up to 60 million afflicted
• Leads to MI, heart failure, stroke and renal disease
• Strong correlation with metabolic syndrome
Blood Pressure Classification according to the JNC 7
• Normal SBP<120 and DBP <80
• Prehypertension SBP 120-139 and DBP 80-89
• Stage 1 Hypertension SBP 140-159 or DBP 90-99
• Stage 2 Hypertension SBP > or equal to 160 or DBP > or equal to 100
Types of Hypertension
• Essential or primary—etiology ?. Contributors include: salt sensitivity, insulin resistance, genetics, sleep apnea, environmental factors,others
• Secondary—renal, adrenal, coarctation of the aorta, steroids, pregnancy
BP review
• Any condition that affects heart rate, stroke volume or peripheral vascular resistance affects arterial blood pressure
• Compensatory mechanisms to maintain balance between hypotension and hypertension
BP review
• BP regulation operates in a negative feedback system
• Baroreceptors and chemoreceptors in the carotid arteries and aortic arch detect changes in arterial blood pressure and in pO2, pCO2 and H+.
• Increased BP results in increased stretch of vessels; activation of vagus and stimulation of medulla via sympathetic or parasympathetic pathways.
BP review
Normally, when the arterial blood pressure is elevated
1. Kidneys will excrete more fluid
2. Fluid loss will result in decreased ECF volume and blood volume
3. Decreased blood flow to the heart will reduce cardiac output
4. Decreased CO reduces arterial blood pressure
BP review cont.
5. Vascular endothelium produces vasodilating substances (nitric oxide, prostacyclin) which reduce blood pressure
Essential Hypertension
• Activation of sympathetic nervous system causing prolonged vasoconstriction
• Activation of RAAS plays integral part as well
• In combination, mechanisms cause prolonged increased vascular resistance; this in turn results in a thickening of vessel walls, less production of nitric oxide (vasodilator) and increased endothelin (increased vascular tone)
Essential Hypertension
• Also felt that hyperinsulinemia and insulin resistance cause endothelial dysfunction by enhanced oxygen free radical-mediated damage and decreased nitric oxide bioavailability. Also is an increased sympathetic response; results in increased vascular tone and constriction
Nonpharmacologic Management of Hypertension
• Weight reduction• Exercise• Salt restriction in diet• Stress reduction• DASH eating plan• Moderation in alcohol intake• If systolic BP cannot be maintained
<140 systolic, tx.
Antihypertensive Drugs
• Classes:1. Angiotensin converting enzyme
inhibitors (ACEI)2. Angiotensin II Receptor Blockers3. Antiadrenergics4. Calcium channel blockers5. Diuretics6. Direct vasodilators7. Renin inhibitors
ACEIs
• Block the enzymes that convert angiotensin I to angiotensin II (potent vasoconstrictor)
• Have action of vasodilation and decrease aldosterone production
• Inhibit breakdown of bradykinins (vasodilator) prolonging effect
ACEIs
• Reverse remodeling of heart muscle and blood vessels
• Reno-protective
• Excellent for heart failure and hypertension
• Improve post-myocardial infarction survival
• Used alone or in combination
ACEIs
• Useful in heart failure as decrease peripheral vascular resistance, cardiac workload and ventricular remodeling
• Captopril is the prototype
• Low incidence of side effects
• Can cause cough or hypotension when first started
ACEIs
• Can cause hyperkalemia
• Should never be used during pregnancy
• May not be as effective in African Americans—may add diuretic in this population to increase efficacy
ACEIs
• Lotensin (benazepril)
• Capoten (captopril)
• Vasotec (enalapril)
• Zestril (lisinopril)
• Altace (ramipril)
• Aceon (perindopril)
Angiotensin II Receptor Blockers (ARBs)
• Block effects of angiotensin II, compete with angiotensin II for tissue binding sites
• Block the receptors in brain, kidneys, heart, vessels and adrenal tissue
ARBs
• Similar end results as seen with ACEIs
• Less likely to cause hyperkalemia
• Persistence of cough is rare
• Prototype is Cozaar (losartan)
Examples of ARBs
• Atacand (candesartan)
• Cozaar (losartan)
• Diovan (valsartan)
• Micardia (telmisartan)
• Benicar (olmesartan)
Antiadrenergics
• Inhibit activity of the sympathetic nervous system
• Effective in decreasing heart rate, force of myocardial contraction, cardiac output, and blood pressure
Antiadrenergics
• Alpha 1 adrenergics receptor blocking agents dilate vessels and decrease peripheral vascular resistance
• Can experience first dose phenomenon with orthostatic hypotension, dizziness, syncope, possible sodium and fluid retention
Antiadrenergics
• Centrally acting sympatholytics stimulate presynaptic alpha 2 receptors in the brain
• Less norepinephrine is released and sympathetic outflow is reduced
• Results in decreased cardiac output, heart rate, peripheral vascular resistance and blood pressure
Antiadrenergics—Alpha 2 agonists
• Centrally acting agents also can result in fluid and sodium retention
• Catapres (clonidine)—orally or by patch
• Tenex (guanfacine)
• Aldomet (methyldopa)
Beta Adrenergic Blockers
• Decrease heart rate, force of myocardial contraction, cardiac output, and renin release from the kidneys
• Drugs of choice with patients with tachycardia, angina, MI, left ventricular hypertrophy and high renin hypertension
• Most are pregnancy category C and D
Beta Blockers
• Inderal (propranolol)
• Corgard (nadolol)
• Lopressor (metoprolol)
• Tenormin (atenolol)
• Kerlone (betaxolol) for glaucoma (ophthalmic), hypertension (orally)
Calcium Channel Blocking Agents
• Useful in hypertension as dilate peripheral arteries and decrease peripheral vascular resistance by relaxing vascular smooth muscle
• Monotherapy or in combination
• Tolerated well in renal failure
Calcium Channel Blocking Agents
• Norvasc (amlodipine)• Cardizem (diltiazem)• Plendil (felodipine)• Procardia (nifedipine)• Calan (verapamil)—may cause
gingival hyperplasia• Note these are also Pregnancy
category C
Diuretics
• Useful in hypertension due to their sodium and water depletion
• May be used as monotherapy• Preferred in the elderly and in African-
Americans• Should be included in any multi-drug
regimen• Thiazide diuretics are most commonly
used diuretics for hypertension
Vasodilators
• Relax smooth muscle in blood vessels resulting in dilation and decreased peripheral vascular resistance
• Reduce afterload so helpful in heart failure
• May cause sodium and water retention
Vasodilators
• Limited effect when used alone. Vasodilating action that lowers BP also stimulates SNS. This, in turn, triggers reflexive compensatory mechanisms that raise BP
Vasodilators
• Corlopam (felodapam)—IV infusion, in hypertensive emergencies, avoid in patients with allergies to sulfites
• Apresoline (hydralazine)—IV, IM or PO. Can cause orthostatic hypotension.
• Rogaine (Minoxidil) po or topical
Ethnic Considerations
• Use calcium channel blockers, diuretics and alpha blockers most effective in African Americans; beta blockers, ACEIs and some ARBs are not as effective as in Caucasians
• Beta blockers have greater effects on Asians than in Caucasians
Hypertensive Emergencies
• Is defined as having end organ damage or diastolic BP of 120 torr or higher
• With oral medications, use captopril 25-50mg po every 1 to 2 hours or clonidine , 0.2mg initially then 0.1mg every hour until diastolic blood pressure falls below 110 torr or 0.7mg has been given
Hypertensive Emergencies
• Nitroglycerine—tolerance develops over 24-48 hours
• Nitroprusside—intraarterial bood pressure should be monitored; metabolized to thiocyanate (precursor to cyanide), a toxic metabolite. Measure serum levels if drug given over 72h. Is photosensitive.
Herbals that affect BP
• Ephedra (ma huang)
• Gingseng
• Yohimbe (for erectile dysfunction)
• caffeine
• In regards to anti-hypertensives, should not abruptly stop any of them. May develop rebound hypertension.
Diuretics
• Indicated for the treatment of edematous and nonedematous conditions
• May be useful in preventing renal failure by sustaining urine flow
• A minimum daily urine output of approx. 400ml is required to remove normal amounts of metabolic end products
Diuretics
• Act on kidneys to decrease absorption of sodium, chloride, water and other substances such as calcium
• Major subclasses are: thiazides, loop and potassium-sparing diuretics
• Each act at different sites of the nephron
Thiazide Diuretics
• Chemically related to sulfonamides so caution with sulfa allergies
• Used in long term management of heart failure and hypertension
• Affect distal convoluted tubule• Effectiveness decreases as the GFR
decreases. Ineffective when GFR is < 30mL/minute. As rising creatinine noted, should use alternative such as loop diuretic.
Thiazide Diuretics
• Diuril (chlorothiazide)
• Hygroton (chlorthalidone)
• HydroDIURIL (hydrochlorothiazide)
Loop Diuretics
• Inhibit sodium and chloride reabsorption in the ascending limb of the Loop of Henle
• Potent diuresis
• Need to restrict dietary sodium when taking these meds
• Lasix (furosemide) is the prototype
Loop Diuretics
• Bumex (bumetamide) more potent than Lasix
• Can give either as oral agents, IV or IM
• Rapid administration can cause deafness
• Must monitor potassium levels, I&0, also weight would be optimum
Potassium Sparing Diuretics
• Act at distal tubule to decrease reabsorption of sodium and potassium excretion
• Spironolactone (prototype) blocks the sodium retaining effects of aldosterone
• Weak diuretics when used alone, often used in combination
• Contraindicated in renal failure
Osmotic Diuretics
• Produce rapid diuresis by increasing the solute load of the glomerular filtrate
• Water is pulled into the intravascular space and excreted via kidneys
• Useful in managing oliguria or anuria• Can prevent acute renal failure
during prolonged surgery, trauma or during chemotherapy
Osmotic Diuretics
• Help reduce increased ICP, reduction of intraocular pressure before certain ophthalmic surgery and for urinary excretion of toxic substances
• Examples include: Osmitrol (mannitol), Ismotic (isosorbide) and Osmoglyn (glycerin)
Drugs that affect Coagulation
• Thrombosis may occur in both arteries and veins
• Arterial thrombi cause disease by obstructing blood flow which can result in tissue ischemia or death
• Venous thrombosis is associated with venous stasis. A venous thrombus is less cohesive than an arterial embolus so venous emboli more prevalent
Hemostasis
• Hemostasis is the prevention or stoppage of blood loss from an injured blood vessel. Process involves vasoconstriction, formation of a platelet plug, activation of clotting factors and growth of fibrous tissue into the blood clot making it more stable.
Clot Lysis
• When clot is being formed, plasminogen is bound to fibrin and becomes a component of the clot
• After tear in blood vessel is repaired, plasminogen is activated by plasminogen activator to produce plasmin. Plasmin (enzyme) breaks down the fibrin mesh and dissolves the clot.
Blood Coagulation Factors
• I fibrinogen• II prothrombin• Ill thromboplastin• IV calcium• V Labile factor• VII proconvertin or stable factor• VIII antihemophilic factor• IX Christmas factor• X Stuart factor• XI plasma thromboplastin antecedent• XII Hageman factor• XIII fibrin-stabilizing factor
Anticoagulants
• Given to prevent formation of new clots and extension of clots already present; do not dissolve clots already present
• Prototype is Heparin
• Heparin may be used in pregnancy
• Weight based dosing per institutional nomogram
Heparin
• Usually will give a loading dose then calculated dosage per 24h; e.g. 15-25units/kg/h for IV dosing
• Monitor aPTT, should be 1.5-2.5 control value—normal value is 35 sec.
• Can cause heparin induced thrombocytopenia
• Reversal agent is protamine sulfate
Heparin
• Combines w/antithrombin III which will inactivate clotting factors IX, X, XI and XII, inhibits conversion of prothrombin to thrombin and prevents thrombus formation. Further affects coagulation by preventing conversion of fibrinogen to fibrin, inhibiting factors V,VIII, XIII and platelet aggregation.
Low Molecular Weight Heparins
• Given subcutaneously in abdomen and do not require close monitoring of blood coagulation tests
• Still should follow platelet counts
• Fragmin (dalteparin)
• Lovenox (enoxaparin)
Coumadin (warfarin)
• Most commonly used oral anticoagulant
• Drug acts in liver to prevent synthesis of vitamin K-dependent clotting factors (II,VII,IX, X). Acts as a competitive antagonist to hepatic use of vitamin K.
• Anticoagulant of choice for long-term maintenance therapy.
Coumadin (warfarin)
• Anticoagulant effects do not occur for 3-5 days after warfarin is started
• Has no effect on platelets or on circulating clotting factors
• Regulated according to the INR (international normalized ratio)
. Therapeutic values are generally 2 to 3.
Coumadin
• INR is based on prothrombin time. Normal baseline or control PT is 12 seconds, therapeutic value is 1.5 times the control or 18 seconds.
• Use of INR has eliminated disparities in different labs
Coumadin
• Dosage reduction in patients with biliary tract disorders, liver disease, malabsorption syndromes, and hyperthyroidism. These conditions increase anticoagulant drug effects by reducing absorption of vitamin K or decreasing hepatic synthesis of clotting factors
• Has multiple, multiple drug interactions• Counteract with vitamin K
Other anticoagulants
• Orgaran (danaparoid)—low molecular weight, heparin-like drug. Given subq. Used in management of hip surgery, ischemic stroke or in those who cannot take heparin. Does not contain heparin.
• Refludan (lepirudin)—used as heparin substitutes
• Arixtra (fondaparinux) –binds to clot bound factor Xa, inhibits thrombon productions
Other Anticoagulants cont.Trade and generic names
• Refludan (lepirudin)
• Argatroban (same generic name)
• Arixtra (fondaparinux)
• Angiomax (bivalirudin)
Antiplatelet Drugs
• Arterial thrombi are composed primarily of platelets
• Antiplatelet drugs act by inhibiting platelet activation, adhesion, aggregation, or procoagulant activity.
• Include drugs that block platelet receptors for thromboxane, ADP, glycoprotein IIb/IIIa and phosphodiesterase inhibitors
Thromboxane A2 Inhibitors
• Work by inhibiting synthesis of prostaglandins. TA inhibitors work by acetylating cyclooxygensase, the enzyme in platelets that synthesizes thromboxane A2 (which causes platelet aggregation).
• ASA is example. It affects the platelets for the life of the platelet.
• NSAIDs not so useful as action wears off as drug wears off
Adenosine Diphosphate Receptor Antagonists
• Ticlid (ticlopidine)• Inhibit platelet aggregation by preventing
ADP-induced binding between platelets and fibrinogen. This reaction inhibits platelet aggregation irreversibly and persist for the lifespan of the platelet (9-10 days)
• Indicated in TIAs• Adverse effects-neutropenia, diarrhea,
skin rashes
Adenosine Diphosphate Receptor Antagonists
• Plavix (clopidogrel)
• Fewer side effects than ASA or Ticlid
• indicated for patients with atherosclerosis for reduction of MI, stroke and vascular death
• Does not need reduction in those with renal problems
Glycoprotein IIb/IIIa Receptor Antagonists
• Reopro (abciximab) is a monoclonal antibody that prevents the binding of fibrinogen, von Willebrand factor and other molecules to GP IIb/IIIa receptors on activated platelets. This action inhibits platelet aggregation.
• Used with percutaneous transluminal coronary angioplasty or removal of atherosclerotic plaque to prevent rethrombosis
Reopro cont.
• Used with aspirin and heparin and is contraindicated in clients who have recently received oral anticoagulants or IV dextran.
• Other contraindications include active bleeding, thrombocytopenia, history of stroke, surgery or trauma within past 6 weeks, uncontrolled hypertension or hypersensitivity.
Other glycoprotein IIb/IIIa Receptor antagonists
• Integrilin (Eptifibatide)
• Aggrastat (tirofiban)
• Similar mechanism of action as Reopro
• Indicated for acute coronary syndrome who are managed medically or by angioplasty or atherectomy
Glycoprotein IIb/IIIba receptor antagonists cont.• Contraindications include: recent
bleeding, history of thrombocytopenia, history of stroke within 30 days, major surgery or severe trauma within past month, severe hypertension, hx of intracranial hemorhage, neoplasm, AV malformation, or aneurysm; platelet ct less than 100,000 or creatinine greater than 2 mg/dL
Phosphodiesterase Inhibitors
• Pletal (cilostazol) increases cAMP which then inhibits platelet aggregation and produces vasodilation. Drug reversibly inhibits platelet aggregation.
• Indicated for intermittent claudication. • Contraindicated in patients with heart
failure• Most common SE is diarrhea and
headache
Miscellaneous
• Persantine (dipyridamole) inhibits platelet aggregation but mechanism is unclear
• Used for prevention of thromboembolism after cardiac valve replacement and is given with Coumadin
Thrombolytics
• Given to dissolve thrombi
• Stimulate conversion of plasminogen to plasmin, an enzyme that breaks down fibrin (the framework of a thrombus)
• Used in severe thromboembolic disease such as MI, PE and ileofemoral thrombosis
Thrombolytics
• Goal is to re-establish blood flow and prevent tissue damage
• Also used to dissolve clots in arterial or venous cannulas or catheters
• Must obtain baseline INR, aPTT, platelet count and fibrinogen
• Will monitor labs 2-3 hours after thrombolytic tx is instituted to determine efficacy
Thrombolytics
• Activase (alteplase), Retavase (reteplase) and TNKase (tenecteplase) are tissue plasminogen activators used mainly in acute MI to dissolve clots.
• Eminase (anistreplase), Streptase (streptokinase) and Abbokinase (urokinase) are enzymes that break down fibrin. Used to lyse coronary clots in acute MI.
Thrombolytics cont.
• Xigris (drotrecogin alfa) is a recombinant version of human activated protein C. Is approved for use in sepsis. Sepsis causes inappropriate blood clot formation and may lead to DIC. Xigris useful in this situation.
Drugs Used to Control Bleeding
• Amicar (aminocaproic acid) and Cyklokapron (tranexamic acid) are used to stop bleeding caused by overdoses of thrombolytic agents
• Trasylol (aprotinin) indicated in patients undergoing CABG . Inhibits breakdown of blood clotting factors.
Important reminders
• Risk factors for thromboembolism1. Obesity2. MI3. Atrial fibrillation4. Prosthetic heart valves5. ASHD6. OCP or HRT7. Hx of DVT or Pe8. Cigarrette smoking9. Immobility
Overview of cholesterol panel
Total cholesterolDesirable-less than 200Borderline high—200-239High—240 or greaterLDLDesired <100Above optimal—100-129Borderline high—130-159High-160-189Very high190
Overview cont.
HDL• High >60• Low <40TriglyceridesNormal—less than 150Borderline high—150-199High--200 to 499Very high—500 or above
Dyslipidemia
• Associated with athersclerosis and numerous pathophysiologic effects
• Elevated total cholesterol, high LDL and low HDL are all risk factors for CAD
• TG indicated excessive caloric intake; excessive proteins and carbohydrates are converted to TG and obesity
Contributors to dyslipidemia
• Hypothyroidism
• Diabetes mellitus
• Alcoholism
• Obesity, beta blockers, oral estrogens, gluccorticoids, sertraline, thiazide diuretics, protease inhibitors
Dyslipidemia cont.
• High dietary intake also increases the conversion of VLDL to LDL cholesterol, and high dietary intake of TG and saturated fat decreases the activity of LDL receptors and increases synthesis of cholesterol.
Types of Lipoproteins
• LDL—unfavorable type. Transports 75% of serum cholesterol to peripheral tissues and the liver. High levels are atherogenic
• VLDL—contains 75% TG and 25% cholesterol. Transports endogenous TG to fat and muscle cells.
• HDL—favorable type. This LP transports cholesterol back to the liver for catabolism and excretion.
Initial Management
• Treat conditions that contribute to elevated lipids (DM, hypothyroidism)
• Start low fat diet• Increase intake of fiber-lowers LDL• Cholesterol lowering margarines• Weight reduction• Exercise—increases HDL• Smoking cessation• HRT
Drug Therapy
• Based on the type of dyslipidemia and its severity
• Classes of agents include: HMB-CoA reductase inhibitors or “statins”, fibrates, bile acid sequestrants and niacin in different forms
• Lovaza
• Zetia
HMG-CoA reductase inhibitors or “statins”
• Inhibit an enzyme (hydroxymethylglutaryl-coenzyme A reductase) required for hepatic synthesis of cholesterol
• Decrease serum cholesterol, LDL, VLDL and TG
• Reach maximal effects within about 6 weeks
Statins cont.
• Drugs also reduce C reactive protein, associated with inflammation and development of CAD
• Undergo extensive first pass metabolism
• Metabolism occurs in liver
Statins cont.
• Adverse effects include:HA, diarrhea, rashes, headaches, constipation, hepatotoxicity and myopathy.
• Should obtain baseline LFTs and then at 6 and 12 weeks after starting then every 6 months
• If serum aminotranferases increase to more than 3x normal, should be reduced or DCed.
Statins cont.
• Do not take with grapefruit juice
• Pregnancy category X
• Examples: Lipitor (atorvastatin), Pravachol (pravastatin), Zocor (simvastatin), Lescol (fluvastatin)
Bile Acid Sequestrants
• Bind bile acids in the intestinal lumen. This causes the bile acids to be excreted in feces and prevents their being recirculated to the liver. Thus, the liver will use cholesterol to produce bile acids thus decreasing serum levels.
Bile Acid Sequestrants
• Especially lower LDL
• Examples are: Questran (cholestyramine) and Welchol (colesevelam)
• Often used with patients already on a statin
• Long term use can affect absorption of folate, Vitamins A,D,E,K
Fibrates
• Tricor (fenofibrate)
• Lopid (gemfibrozil)
• These drugs increase oxidation of fatty acids in liver and muscle tissue thus decreasing hepatic production of TG, VLDL and increase HDL.
• Most effective drugs for reducing TG.
Fibrates cont.
• Can cause hepatotoxicity
• Main side effects include: diarrhea, GI discomfort, cause gallstones, interact with Coumadin
Niacin (nicotinic acid)
• Decreases both cholesterol and triglycerides
• Bottom line—decreases hepatic synthesis of TG and secretion of VLDL (which leads to decreased production of LDL)
• Need high doses for efficacy
Niacin
• Side effects include: flushing, pruritus, gastric irritation. May cause hyperglycemia, hyperuricemia, elevated hepatic aminotransferase enzymes and hepatitis.
• Can reduce flushing by starting with low doses, taking dose with meals, and taking ASA 325mg thirty minutes before taking dose
Niacin
• More effective in preventing heart disease when used in combination with another dyslipidemic such as a bile acid sequestrant or a fibrate.