1、ANTIHYPERTENSIVES, DIURETICS, ANTICOAGULANTS AND DYSLIPIDEMICS,PHARMACOLOGY NUR 3703 BY LINDA SELF,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 accordin
2、g to the JNC 7,Normal SBP or equal to 160 or DBP or equal to 100,Types of Hypertension,Essential or primaryetiology ?. Contributors include: salt sensitivity, insulin resistance, genetics, sleep apnea, environmental factors,others Secondaryrenal, adrenal, coarctation of the aorta, steroids, pregnanc
3、y,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 chemore
4、ceptors 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 b
5、lood pressure is elevated Kidneys will excrete more fluid Fluid loss will result in decreased ECF volume and blood volume Decreased blood flow to the heart will reduce cardiac output Decreased CO reduces arterial blood pressure,BP review cont.,5. Vascular endothelium produces vasodilating substances
6、 (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 i
7、n 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 n
8、itric 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 can
9、not be maintained 140 systolic, tx.,Antihypertensive Drugs,Classes: Angiotensin converting enzyme inhibitors (ACEI) Angiotensin II Receptor Blockers Antiadrenergics Calcium channel blockers Diuretics Direct vasodilators Renin inhibitors,ACEIs,Block the enzymes that convert angiotensin I to angiotens
10、in 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-myocard
11、ial 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 hyperk
12、alemia Should never be used during pregnancy May not be as effective in African Americansmay add diuretic in this population to increase efficacy,ACEIs,Lotensin (benazepril) Capoten (captopril) Vasotec (enalapril) Zestril (lisinopril) Altace (ramipril) Aceon (perindopril),Angiotensin II Receptor Blo
13、ckers (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 (
14、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
15、,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-Alpha 1,Cardura (doxazosin) Minipress (p
16、razosin) Hytrin (terazosin),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,Antia
17、drenergicsAlpha 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 ki
18、dneys 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
19、), 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 (amlodipi
20、ne) 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-Am
21、ericans Should be included in any multi-drug regimen Thiazide diuretics are most commonly used diuretics for hypertension,Diuretics,Hydrodiuril (HCTZ),Vasodilators,Relax smooth muscle in blood vessels resulting in dilation and decreased peripheral vascular resistance Reduce afterload so helpful in h
22、eart 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, av
23、oid 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 AR
24、Bs 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 initia
25、lly then 0.1mg every hour until diastolic blood pressure falls below 110 torr or 0.7mg has been given,Hypertensive Emergencies,Nitroglycerinetolerance develops over 24-48 hours Nitroprussideintraarterial bood pressure should be monitored; metabolized to thiocyanate (precursor to cyanide), a toxic me
26、tabolite. Measure serum levels if drug given over 72h. Is photosensitive.,Hypertensive Emergencies,Corlopam (felodopam)IV infusion, use short term.,Herbals that affect BP,Ephedra (ma huang) Gingseng Yohimbe (for erectile dysfunction) caffeine,In regards to anti-hypertensives, should not abruptly sto
27、p 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 produ
28、cts,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,Diuretics,Used to manage: Edema and ascites Management of heart failure
29、 Hypertension,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 n
30、oted, 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 sodiu
31、m 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 d
32、istal 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
33、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 intraoc
34、ular 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 obstructin
35、g 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. Pr
36、ocess 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
37、 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 antihemophi
38、lic 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 b
39、e 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 valuenormal value is 35 sec. Can cause heparin induced thrombocytopenia Reversal agen
40、t 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
41、, 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 a
42、cts 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 sta
43、rted 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 con
44、trol 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 dec
45、reasing 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
46、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
47、),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 inhibitor
48、s,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 no
49、t 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
50、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,
