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Chapter 20
Drugs Affecting Circulation:
Antihypertensives, Antianginals,
Antithrombotics
Mosby items and derived items © 2008, 2002 by Mosby, Inc., an affiliate of Elsevier Inc.
Epidemiology and Etiology of
Hypertension
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Primary: Unknown etiology
Secondary: Due to known disease process
Adversely affects numerous organs
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Diagnosis:
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Termed cardiovascular disease (CVD)
Two or more seated BP taken on different days
Increased risk of:
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Left ventricular (LV) hypertrophy, angina, myocardial
infarction (MI), heart failure, stroke, peripheral arterial
disease (PAD), retinopathy, and renal failure
Mosby items and derived items © 2008, 2002 by Mosby, Inc., an affiliate of Elsevier Inc.
Pathophysiology of Hypertension
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Arterial blood pressure
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Preload is major factor in systolic blood
pressure (SBP)
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Product of cardiac output (CO) and total
resistance
Affects venous capacitance
Afterload is major factor in diastolic blood
pressure (DBP)
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Hypertensive Crisis
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Patient with BP > 180/120 mmHg
Hypertensive urgency
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No signs/symptoms of organ complication
Hypertensive emergency
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Acute, chronic, or progressive organ injury
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Hypertension Pharmacotherapy
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First-line agents:
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Angiotensin-converting enzyme inhibitors (ACEIs)
Angiotensin II receptor blockers (ARBs)
Calcium channel blockers (CCBs)
β Blockers
Thiazide-type diuretics
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Hypertension Pharmacotherapy
(cont’d)
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Second-line agents
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Vasodilators
α Blockers
α2 Agonists
Antiadrenergics
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Hypertension Pharmacotherapy
(cont’d)
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Angiotensin-converting enzyme inhibitors
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Suppress renin-angiotensin-aldosterone system
• Block conversion of angiotensin I to angiotensin II
Hemodynamic effect
• Reduce peripheral arterial resistance (PAR)
• Increase CO
• Increase renal blood flow
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Hypertension Pharmacotherapy
(cont’d)
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Indicated for:
• Hypertension (HTN), heart failure, systolic dysfunction,
MI prevention, LV dysfunction, and diabetic neuropathy
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Generally decrease SBP and DBP 15-25%
Most common side effect is dry cough
Significant interaction with nonsteroidal
antiinflammatory drugs (NSAIDs)
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Hypertension Pharmacotherapy
(cont’d)
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Angiotensin II receptor blockers
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Angiotensin II type 1 receptor agonists
• Receptors found in vascular smooth muscle, myocardium,
brain, kidney, liver, uterus, adrenal glands
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Indicated for HTN and treatment of heart failure
Slightly “weaker” than ACEIs
Side effects: Orthostatic hypotension, hyperkalemia,
neutropenia, nephrotoxicity, and fetotoxicity
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Hypertension Pharmacotherapy
(cont’d)
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Calcium channel blockers
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Cause coronary and peripheral vasodilation via Lchannel blockade
Verapamil and diltiazem
• Negative chronotropic and inotropic effects
• Long-acting formulations (target circadian rhythm)
• High incidence of constipation
• Side effects
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Hypertension Pharmacotherapy
(cont’d)
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β Blockers
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Method of action
Indications
• Essential HTN, angina, dysrhythmias, MI prevention,
chronic heart failure
• Also: Migraine prophylaxis and alcohol withdrawal
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May induce bronchospasm and render β-agonist
ineffective
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Hypertension Pharmacotherapy
(cont’d)
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Diuretics
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Five classes
• Thiazide and thiazide-like agents
• Loop diuretics
• K-sparing agents
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Used for HTN
• Carbonic anhydrase inhibitors (CAIs)
• Osmotics
 Interact with NSAIDs
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Hypertension Pharmacotherapy
(cont’d)
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Potassium-sparing diuretics
• Weak if used alone
• Additive effect with thiazides
• Amiloride (Midamor) and triamterene (Dyrenium)
• Side effects
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Hypertension Pharmacotherapy
(cont’d)
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Thiazide and thiazide-like diuretics
• Increase Na and Cl excretion
• Dose-ceiling effect
• 2 to 4 weeks to elicit full effect
• Side effects
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Hypertension Pharmacotherapy
(cont’d)
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Loop diuretics
• Decrease Na reabsorption at ascending limb of loop of
Henle
• Indicated for chronic heart failure, ascites, renal failure,
pulmonary edema, hypercalcemia, hypermagnesemia,
syndrome of inappropriate antidiuretic hormone
• Second-line treatment for management of HTN
• Cause frequent urination
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Hypertension Pharmacotherapy
(cont’d)
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Aldosterone antagonists
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Spironolactone (Aldactone) and Eplerenone (Inspra)
Spironolactone is weak, often used with other
antihypertensives
• Adverse effects: Impotence, gynecomastia, deep voice,
menstrual irregularities, hirsutism, gastrointestinal upset, rash,
drowsiness
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Eplerenone
• Indicated for HTN and post-MI heart failure
• Minimal adverse sexual side effects
• Higher risk of hyperkalemia
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Hypertension Pharmacotherapy
(cont’d)
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Centrally acting adrenergic agents
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Affect CO and peripheral resistance
Negative inotrope/negative chronotrope
α2 Agonists are effective, but riddled with side
effects
• Clonidine transdermal is most effective and least toxic
Mosby items and derived items © 2008, 2002 by Mosby, Inc., an affiliate of Elsevier Inc.
Hypertension Pharmacotherapy
(cont’d)
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α1-Adrenergic antagonists
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Cause arterial and venous dilation
• Decrease preload and afterload
First-dose phenomenon
• Initial doses low and at bedtime
Indicated for HTN, benign prostatic hyperplasia,
heart failure, and Raynaud’s vasospasm
Mosby items and derived items © 2008, 2002 by Mosby, Inc., an affiliate of Elsevier Inc.
Hypertension Pharmacotherapy
(cont’d)
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Antiadrenergic agents
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Second-line drugs
Reserpine
• Depletes postganglionic norepinephrine
• May cause: Sedation, depression, psychosis, peptic ulcers,
nasal stuffiness
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Guanethidine (Ismelin) and Guanadrel (Hylorel)
• Substitute neurotransmitters
• May cause orthostatic hypotension, sexual dysfunction,
explosive diarrhea
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Hypertension Pharmacotherapy
(cont’d)
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Vasodilators
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Hydralazine (Apresoline) and minoxidil (Rogaine,
Loniten)
 Second-line treatment for HTN because of side
effects
 Act on vascular smooth muscle to decrease total
peripheral resistance
• May cause reflex tachycardia, renin release, increased
CO
• Often given with β blocker and loop diuretic
Mosby items and derived items © 2008, 2002 by Mosby, Inc., an affiliate of Elsevier Inc.
Epidemiology, Etiology, and
Pathophysiology of Angina
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“Chest pain”
Symptom of myocardial ischemia
Imbalance of myocardial O2 supply and
demand
May present as:
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Heavy weight or pressure on chest
 Burning sensation
 Shortness of breath (SOB)
 Pain over sternum, left shoulder, or lower jaw
Mosby items and derived items © 2008, 2002 by Mosby, Inc., an affiliate of Elsevier Inc.
Pharmacotherapy for Angina
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Nitrates
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Nitroglycerin dilates coronary arteries and
collaterals (mostly venous effect)
Indications: Angina, acute MI, HTN
Formulations: Oral, IV, ointment, transdermal,
translingual, sublingual
• Sublingual: Q 5 minutes x 3, then seek care
Adverse effects: Tachycardia, palpitations,
hypotension, dizziness, flushing, headache
Mosby items and derived items © 2008, 2002 by Mosby, Inc., an affiliate of Elsevier Inc.
Pharmacotherapy for Angina (cont’d)
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Ranolazine (Ranexa)
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Indicated for chronic angina not responding to
other medications
Shifts energy production from fatty acid oxidation
to glucose oxidation (uses less O2)
500 mg BID (maximum, 1 g BID)
Contraindicated in hepatic dysfunction
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Antithrombotic Agents
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Formation and elimination of acute coronary
thrombus
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Formation initiated by injury to endothelium
Platelets adhere to site of injury, release chemicals
that cause further aggregation, forming unstable
thrombus
Eventually forms insoluble fibrin clot
• Must be removed by fibrinolytic system for homeostasis
to be maintained
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Antithrombotic Agents (cont’d)
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Anticoagulant agents
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Heparins: Unfractionated heparin and low
molecular weight heparin
• Indicated for venous thromboembolism, pulmonary
embolism, atrial fibrillation (AF), disseminated
intravascular coagulation (DIC), and peripheral arterial
embolism
• Extracted from porcine intestinal mucosa
Mosby items and derived items © 2008, 2002 by Mosby, Inc., an affiliate of Elsevier Inc.
Antithrombotic Agents (cont’d)
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Anticoagulant agents (cont’d)
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Heparins: Unfractionated heparin and low
molecular weight heparin (cont’d)
• Goal: Balance unwanted clotting with risk of hemorrhage
• Side effects: Bleeding, thrombocytopenia, hyperkalemia,
osteoporosis, increased liver enzyme tests (LETs)
• Antidote: Protamine sulfate
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Antithrombotic Agents (cont’d)
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Anticoagulant agents (cont’d)
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Direct thrombin inhibitors
• Desirudin (Iprivask): Indicated for deep vein thrombosis
(DVT)
• Bivalirudin (Angiomax): Indicated for unstable angina
• Argatroban and lepirudin (Refludan): Used for
anticoagulation of patients with heparin-induced
thrombocytopenia type 2 (HIT-2)
• Common adverse side effect: Hemorrhage
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Antithrombotic Agents (cont’d)
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Anticoagulant agents (cont’d)
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Warfarin (Coumadin)
• Oral anticoagulant for venous thrombosis, pulmonary
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embolism (PE), AF, valve replacement, coronary
occlusion
Daily dosing (delayed onset of 3-5 days)
International normalized ratio (INR) is standard for
monitoring therapy
Hemorrhage is common side effect
Many drugs may increase/decrease effects
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Antithrombotic Agents (cont’d)
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Antiplatelet agents
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Aspirin
• Reduces platelet aggregation by inhibition of
prostaglandin production
• Antithrombotic indications: Reduce risk of thrombosis,
transient ischemic attack (TIA), or stroke
Mosby items and derived items © 2008, 2002 by Mosby, Inc., an affiliate of Elsevier Inc.
Antithrombotic Agents (cont’d)
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Antiplatelet agents (cont’d)
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Aspirin (cont’d)
• Side effects: Peptic ulcer, renal dysfunction, HTN,
tinnitus, pulmonary dysfunction, and bleeding
• Ibuprofen inhibits pharmacological effect; concurrent
NSAID use may cause fatal gastropathy
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Antithrombotic Agents (cont’d)
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Antiplatelet agents (cont’d)
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Dipyridamole
• Vasodilator and platelet adhesion inhibitor
• Indicated as an adjunct to warfarin in prevention of
postoperative thromboembolic complications of cardiac
valve replacement
• May potentiate effect of adenosine
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Antithrombotic Agents (cont’d)
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Antiplatelet agents (cont’d)
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Clopidogrel (Plavix)
• Platelet aggregation inhibitor
• Indications: History of MI, stroke, PAD, acute coronary
•
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•
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syndrome
Slightly more effective than aspirin (except for stroke
prophylaxis)
Metabolized by liver
Steady state in 3 to 7 days
75 mg QD (plus aspirin)
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300-mg loading dose for acute coronary syndrome (ACS)
Mosby items and derived items © 2008, 2002 by Mosby, Inc., an affiliate of Elsevier Inc.
Antithrombotic Agents (cont’d)
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Antiplatelet agents (cont’d)
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Ticlopidine
• Platelet aggregation inhibitor
• Indicated for stroke
• More effective than aspirin
• Steady state in 14 to 21 days
• Metabolized by liver
• Risk of life-threatening blood dyscrasias
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Use only if aspirin/clopidogrel are unacceptable
Mosby items and derived items © 2008, 2002 by Mosby, Inc., an affiliate of Elsevier Inc.
Antithrombotic Agents (cont’d)
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Antiplatelet agents (cont’d)
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Cilostazol and pentoxifylline
• Cause vasodilation and inhibition of platelet aggregation
• Indicated for PAD pain
• Clinical benefits may take up to 12 weeks
• Transient adverse effects: Headache, diarrhea,
dizziness, palpitations
• 100 mg BID on an empty stomach
Mosby items and derived items © 2008, 2002 by Mosby, Inc., an affiliate of Elsevier Inc.
Antithrombotic Agents (cont’d)
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Antiplatelet agents (cont’d)
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Glycoprotein IIb/IIIa inhibitors
• Indicated for ACS
• Abciximab (ReoPro) is “drug of choice”
• Not available in oral formulation (ineffective)
• Bleeding is most common adverse side effect
Mosby items and derived items © 2008, 2002 by Mosby, Inc., an affiliate of Elsevier Inc.
Antithrombotic Agents (cont’d)
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Thrombolytic agents
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Indicated for PE, ischemic stroke, and acute ST
segment elevation MI
Agents: Streptokinase (second line), alteplase,
reteplase, and tenecteplase
• Therapy should begin within 12 hours of symptoms
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Antithrombotic Agents (cont’d)
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Thrombolytic agents (cont’d)
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Contraindications: Internal bleeding, aortic
dissection, head injury or stroke in last 3 months,
HTN, anticoagulant use
Bleeding is most common adverse effect
• Gastrointestinal, genitourinary, respiratory tract,
retroperitoneal, intracranial
Mosby items and derived items © 2008, 2002 by Mosby, Inc., an affiliate of Elsevier Inc.