Drugs Affecting Circulation

• Drugs affecting circulation include antihypertensives, antianginals, and antithrombotics, crucial in acute, outpatient, and home care settings.

Key Terms

• Antithrombotics: Prevent or break up blood clots, including anticoagulants, antiplatelets, and thrombolytics.
• Arterial Blood Pressure: Hemodynamically defined as systemic vascular resistance multiplied by cardiac output (heart rate × stroke volume).
• Cardiovascular Disease (CVD): Damage to the heart, blood vessels, or circulation, affecting the brain, kidneys, and eyes.
• Chronotropic: Influences the rate of rhythmic movements, especially heartbeat.
• Circadian Rhythm: Biological variations within a 24-hour cycle.
• Creatinine Clearance (CrCl): Renal clearance of endogenous creatinine, approximating glomerular filtration rate (GFR), used for drug dosage.
• D-dimers: Fragments from fibrinolysis, indicating fibrinolysis presence.
• Dose-Ceiling Effect: Maximum drug dose beyond which therapeutic effect plateaus but toxicity increases.
• Fibrin Split/Fibrinogen Degradation Products (FDPs): Peptides from plasmin on fibrinogen/fibrin, acting as anticoagulants causing bleeding if uncontrolled.
• Glomerular Filtration Rate (GFR): Volume filtered by the kidney, 90% of creatinine clearance.
• Hypertensive Emergency: Blood pressure exceeds 180/120 mm Hg with acute organ injury.
• Hypertensive Urgency: Blood pressure exceeds 180/120 mm Hg without acute organ complications.
• Inotropes: Influence muscle contractility, especially heart muscle.
• Intrinsic Sympathomimetic Activity (ISA): Ability to activate and block adrenergic receptors, stimulating the sympathetic nervous system.
• Renin: Enzyme from the kidney converting angiotensinogen to angiotensin I due to reduced renal blood flow.

Hypertension

• High blood pressure is defined as ≥140/90 mm Hg.
• Primary hypertension lacks a known cause (essential hypertension).
• Secondary hypertension results from an identifiable disease.
• Hypertension adversely affects the heart, brain, kidneys, and eyes, leading to cardiovascular disease (CVD).
• Diagnosis requires two or more seated blood pressure readings on different days.
• Increased risk includes left ventricular hypertrophy, angina, myocardial infarction (MI), heart failure, stroke, peripheral arterial disease (PAD), retinopathy, and renal failure.
• Arterial blood pressure is the product of cardiac output (CO) and total resistance.
• Preload is a major determinant of systolic blood pressure (SBP), affecting venous capacitance.
• Afterload is a major determinant of diastolic blood pressure (DBP).

Hypertensive Crisis

• Hypertensive crisis involves blood pressure >180/120 mmHg.
• Hypertensive urgency: No signs/symptoms of organ complication, potentially with severe headaches, SOB, nosebleeds, and anxiety, managed over 24-48 hours.
• Hypertensive emergency: Acute, chronic, or progressive organ injury necessitating ICU admission and blood pressure monitoring.

Hypertension Pharmacotherapy

• First-line agents: Angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), β-blockers, and thiazide-type diuretics.
• Second-line agents: Vasodilators, α-blockers, α2-agonists, and antiadrenergics.

Angiotensin-Converting Enzyme Inhibitors (ACEIs)

• ACEIs suppress the renin–angiotensin–aldosterone system.
• They block the conversion of angiotensin I to angiotensin II.
• Reduce peripheral arterial resistance (PAR), increase CO, and increase renal blood flow.
• Indicated for hypertension (HTN), heart failure, systolic dysfunction, MI prevention, LV dysfunction, and diabetic neuropathy.
• Effective alone or with thiazide-type diuretics.
• Typically decrease SBP and DBP by 15–25%.
• Common side effect: Dry cough, rarely angioedema.
• Do not induce glucose intolerance, hyperlipidemia, or hyperuricemia.
• Significant interaction with nonsteroidal antiinflammatory drugs (NSAIDs).

Angiotensin II Receptor Blockers (ARBs)

• Receptors located in vascular smooth muscle, myocardium, brain, kidney, liver, uterus, and adrenal glands.
• Indicated for HTN and heart failure treatment.
• Side effects: Orthostatic hypotension, hyperkalemia, neutropenia, nephrotoxicity, and fetotoxicity.

Direct Renin Inhibitors (DRI)

• Act by inhibiting renin.
• Can be used alone or with other antihypertensive agents.
• Aliskiren is the only DRI available.
• Side effects: Diarrhea, headache, dizziness, fatigue, upper respiratory track infection, nasopharyngitis, and back pain.

Calcium Channel Blockers (CCBs)

• Cause coronary and peripheral vasodilation via L-channel blockade.
• Verapamil and diltiazem have negative chronotropic and inotropic effects and a high incidence of constipation, with long-acting formulations targeting circadian rhythm.
• Amlodipine, felodipine, isradipine, nifedipine, and nisoldipine have negligible chronotropic effects (except nifedipine).
• Only sustained-release dosage forms of nifedipine are indicated for hypertension.
• Amlodipine and felodipine may be used in patients with heart failure.

β-Blockers

• Block β-receptors on renal juxtaglomerular cells and myocardial/central nervous system β-receptors.
• Indications include HTN, angina pectoris, cardiac dysrhythmias, MI prevention, chronic heart failure, and pheochromocytoma, also for migraine prophylaxis and alcohol withdrawal.
• May induce bronchospasm and render β-agonists ineffective.

Aldosterone Antagonists

• Spironolactone (Aldactone) and eplerenone (Inspra).
• Spironolactone, a weak diuretic, is used with other antihypertensives, indicated for hepatic cirrhosis, primary hyperaldosteronism, hypokalemia, heart failure, and HTN.
• Spironolactone adverse effects include impotence, gynecomastia, deep voice, menstrual irregularities, hirsutism, gastrointestinal upset, rash, and drowsiness.
• Eplerenone is indicated for HTN and post-MI heart failure, with minimal adverse sexual side effects but a higher risk of hyperkalemia.

Centrally Acting Adrenergic Agents

• α2-Agonists affect CO and peripheral resistance.
• They have negative inotropic/chronotropic effects.
• α2-Agonists are effective but have a high incidence of anticholinergic-like effects.
• Clonidine transdermal is the most effective and least toxic.

α1-Adrenergic Antagonists

• Selectively block postsynaptic α1-receptors.
• Cause arterial and venous dilation, decreasing preload and afterload.
• First-dose phenomenon manifests with orthostatic hypotension, tachycardia, palpitations, dizziness, headaches, and syncope; initial doses should be low and given at bedtime.
• Indicated for HTN, benign prostatic hyperplasia, heart failure, and Raynaud’s vasospasm.

Antiadrenergic Agents

• Second-line drugs, such as reserpine, deplete postganglionic norepinephrine, may cause sedation, depression, psychosis, peptic ulcers, and nasal stuffiness.
• Guanethidine (Ismelin) and guanadrel (Hylorel) substitute neurotransmitters and may cause orthostatic hypotension, sexual dysfunction, and explosive diarrhea.
• Antihypertensive effects are diminished when combined with tricyclic antidepressants, amphetamines, or ephedrine.

Vasodilators

• Hydralazine (Apresoline) and minoxidil (Rogaine, Loniten) are second-line treatments for HTN due to side effects.
• They act on vascular smooth muscle to decrease total peripheral resistance.
• May cause reflex tachycardia, renin release, and increased CO.
• Often given with a β-blocker and loop diuretic.

Angina

• Chest pain is a symptom of myocardial ischemia due to an imbalance of myocardial O2 supply and demand.
• May present as a heavy weight or pressure on the chest, burning sensation, shortness of breath (SOB), or pain over the sternum, left shoulder, or lower jaw.

Pharmacotherapy for Angina

• Nitrates: Nitroglycerin reduces myocardial oxygen demand by dilating coronary arteries and collaterals (mostly venous effect).
• Indications: Angina, acute MI, HTN.
• Formulations: Oral, IV, ointment, transdermal, translingual, sublingual.
• Sublingual administration: Every 5 minutes × 3, then seek care.
• Adverse reactions: Tachycardia, palpitations, hypotension, dizziness, flushing, and headache.
• Ranolazine (Ranexa): Indicated for chronic angina not responding to other medications.
• Shifts energy production from fatty acid oxidation to glucose oxidation (uses less O2).
• Dosage: 500 mg BID (maximum, 1 g BID).
• Adverse reactions: Dizziness, palpitations, headache, constipation, nausea, pain, and peripheral edema.
• Contraindicated in hepatic dysfunction.

Antithrombotic Agents

• Prevent or break up blood clots.
• Formation and elimination of acute coronary thrombus begin with injury to the endothelium.
• Platelets adhere, release chemicals causing further aggregation, forming an unstable thrombus, which eventually forms an insoluble fibrin clot.
• The fibrinolytic system must remove clots for homeostasis.
• Three categories: Anticoagulants, antiplatelets, and thrombolytics.

Anticoagulant Agents

• 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.
• Goal: Balance unwanted clotting with the risk of hemorrhage.
• Side effects: Bleeding, thrombocytopenia, hyperkalemia, osteoporosis, increased liver enzyme tests (LETs).
• Antidote: Protamine sulfate.
• Direct thrombin inhibitors: Desirudin (Iprivask) for deep vein thrombosis (DVT), Bivalirudin (Angiomax) for unstable angina, and Argatroban and lepirudin (Refludan) for anticoagulation of patients with heparin-induced thrombocytopenia type 2 (HIT-2).
• Common adverse side effect: Hemorrhage.
• Warfarin (Coumadin): Oral anticoagulant for venous thrombosis, pulmonary embolism (PE), atrial fibrillation, valve replacement, and coronary occlusion.
• Daily dosing with a delayed onset of 3–5 days.
• International normalized ratio (INR) is the standard for monitoring therapy.
• Hemorrhage is a common side effect.
• Many factors may increase/decrease effects, including diet, disease states, and drugs.

Antiplatelet Agents

• Aspirin: In platelets, prostaglandin derivative thromboxane A2 is a major inducer of platelet aggregation and vasoconstriction.
• Reduces platelet aggregation by inhibiting prostaglandin production.
• Antithrombotic indications: Reduce the risk of thrombosis, transient ischemic attack (TIA), or stroke.
• Side effects: Peptic ulcer, renal dysfunction, HTN, tinnitus, pulmonary dysfunction, and bleeding.
• Ibuprofen inhibits pharmacological effect; concurrent NSAID use may cause fatal gastropathy.
• Dipyridamole: Vasodilator and platelet adhesion inhibitor.
• Indicated only as an adjunct to warfarin in the prevention of postoperative thromboembolic complications of cardiac valve replacement.
• May potentiate the effect of adenosine.
• Adverse reactions: Headache, dizziness, hypotension, and distress.
• Clopidogrel (Plavix): A prodrug that must undergo a two-step hepatic conversion.
• Platelet aggregation inhibitor.
• Indications: History of MI, stroke, PAD, acute coronary syndrome (ACS).
• Slightly more effective than aspirin (except for stroke prophylaxis).
• Metabolized by the liver with steady state in 3 to 7 days.
• Dosage: 75 mg QD (plus aspirin) or a 300-mg loading dose for ACS.
• Ticlopidine: Platelet aggregation inhibitor, indicated for stroke.
• More effective than aspirin, with steady state in 14–21 days.
• Metabolized by the liver, but has a risk of life-threatening blood dyscrasias, so use only if aspirin and clopidogrel are unacceptable.
• Prasurgel: A prodrug indicated for the prevention of thrombosis in patients with ACS undergoing percutaneous coronary intervention.
• In combination with aspirin decreases nonfatal MI but has an increased bleeding risk.
• Onset of action can be seen as early as 30 minutes.
• Adverse reaction: Bleeding.
• 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, and palpitations.
• Dosage: 100 mg BID on an empty stomach.
• Glycoprotein IIb/IIIa inhibitors: Indicated for ACS.
• Abciximab (ReoPro) is the “drug of choice.”
• Not available in oral formulation (ineffective).
• Bleeding is the most common adverse side effect.

Thrombolytic Agents

• 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.
• Thrombolytics are preferred to percutaneous coronary intervention (PCI) when patients present within 3 hours of symptom onset and door-to-primary PCI time will be greater than 90 minutes.
• Contraindications: Internal bleeding, aortic dissection, head injury or stroke in the last 3 months, HTN, and anticoagulant use.
• Bleeding is the most common adverse effect, including gastrointestinal, genitourinary, respiratory tract, retroperitoneal, and intracranial.