Drugs Affecting Circulation

• Drugs affecting circulation include antihypertensives, antianginals, and antithrombotics

Key Terms

• Antithrombotics: Prevent or break up blood clots in conditions like thrombosis or embolism, including anticoagulants, antiplatelets, and thrombolytics.
• Arterial blood pressure (blood pressure): Defined as the product of systemic vascular resistance and cardiac output (heart rate × stroke volume).
• Cardiovascular disease (CVD): Damage to the heart, blood vessels, or circulation, including damage to the brain, kidney, and eyes.
• Chronotropic: Influencing the rate of rhythmic movements, such as heartbeat.
• Circadian rhythm: Human biologic variations of rhythm within a 24-hour cycle.
• Creatinine clearance (CrCl): Measurement of the renal clearance of endogenous creatinine per unit of time, approximating glomerular filtration rate (GFR), used for drug dosage guidelines.
• D-dimers: Degradation fragments of cross-linked fibrin polymer during plasmin-mediated fibrinolysis; levels increase after fibrinolysis onset.
• Dose-ceiling effect: Maximum drug dose beyond which it no longer exerts a therapeutic effect, but its toxic effect increases.
• Fibrin split or fibrinogen degradation products (FDPs): Small peptides resulting after plasmin action on fibrinogen and fibrin, acting as anticoagulant substances that can cause bleeding if fibrinolysis is uncontrolled.
• Glomerular filtration rate (GFR): Volume of water filtered from plasma by the kidney into Bowman capsules per unit of time.
• Hypertensive emergency: Blood pressure greater than 180/120 mm Hg, with acute, progressing target organ injury.
• Hypertensive urgency: Blood pressure greater than 180/120 mm Hg without acute target organ complications.
• Inotropes: Drugs influencing the contractility of a muscle (heart).
• Intrinsic sympathomimetic activity (ISA): Ability to activate and block adrenergic receptors, producing a net stimulatory effect on the sympathetic nervous system.
• Renin: Enzyme released by the kidney that converts angiotensinogen into angiotensin I.

Hypertension

• High blood pressure is defined as ≥140/90 mm Hg.
• Primary hypertension: Has an unknown etiology (essential hypertension).
• Secondary hypertension: Results from a known disease process.
• Adversely affects the heart, brain, kidney, and eyes, leading to cardiovascular disease (CVD).
• Diagnosis requires two or more seated blood pressure readings taken on different days.
• Increases the risk of left ventricular (LV) hypertrophy, angina, myocardial infarction (MI), heart failure, stroke, peripheral arterial disease (PAD), retinopathy, and renal failure.

Pathophysiology of Hypertension

• Arterial blood pressure is the product of cardiac output (CO) and total resistance.
• Preload is the major factor in systolic blood pressure (SBP), affecting venous capacitance.
• Afterload is the major factor in diastolic blood pressure (DBP).

Hypertensive Crisis

• Defined as blood pressure > 180/120 mmHg.
• Hypertensive urgency: No signs or symptoms of organ complication; may involve severe headaches, SOB, nosebleeds, or severe anxiety, and is controlled over 24-48 hours.
• Hypertensive emergency: Involves acute, chronic, or progressive organ injury, requiring 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

• They suppress the renin–angiotensin–aldosterone system by blocking the conversion of angiotensin I to angiotensin II.
• Hemodynamic effects: 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, generally decreasing SBP and DBP by 15–25%.
• The most common side effect is a dry cough, less commonly angioedema.
• Do not induce glucose intolerance, hyperlipidemia, or hyperuricemia.
• There is a significant interaction with nonsteroidal antiinflammatory drugs (NSAIDs).

Angiotensin II Receptor Blockers

• Receptors are found in vascular smooth muscle, myocardium, brain, kidney, liver, uterus, and adrenal glands.
• Indicated for HTN and treatment of heart failure.
• Slightly weaker than ACEIs.
• Side effects: Orthostatic hypotension, hyperkalemia, neutropenia, nephrotoxicity, and fetotoxicity.

Direct Renin Inhibitors (DRI)

• Act by inhibiting renin.
• Can be used alone or in combination 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

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

β-Blockers

• Act by blocking the β-receptors on the renal juxtaglomerular cells, myocardial β-receptors, and central nervous system β-receptors.
• Indications: HTN, angina pectoris, cardiac dysrhythmias, MI prevention, chronic heart failure, and pheochromocytoma
• Also used for migraine prophylaxis and alcohol withdrawal.
• May induce bronchospasm and render β-agonist ineffective.

Aldosterone Antagonists

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

Centrally Acting Adrenergic Agents

• α2-Agonists.
• Affect CO and peripheral resistance.
• Negative inotrope/negative chronotrope.
• α2-Agonists are effective but riddled with side-effects, having 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 taken at bedtime.
• Indicated for HTN, benign prostatic hyperplasia, heart failure, and Raynaud’s vasospasm.

Antiadrenergic Agents

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

Vasodilators

• 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, and increased CO.
• Often given with a β-blocker and loop diuretic.

Angina

• A symptom of myocardial ischemia caused by an imbalance of myocardial O2 supply and demand.
• May present as 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, and HTN.
• Formulations: Oral, IV, ointment, transdermal, translingual, and sublingual.
• Sublingual administration: Q 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).
• 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.
• Formation is initiated by injury to the endothelium.
• Platelets adhere to the site of injury, release chemicals that cause further aggregation, forming an unstable thrombus.
• Eventually forms an insoluble fibrin clot.
• Must be removed by the fibrinolytic system for homeostasis to be maintained.
• Three categories: Anticoagulants, antiplatelets, and thrombolytics.

Anticoagulant Agents

• Heparins: Unfractionated heparin and low-molecular-weight heparin.
• Indications: 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, and increased liver enzyme tests (LETs).
• Antidote: Protamine sulfate.
• 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.
• Warfarin (Coumadin):
• Oral anticoagulant for venous thrombosis, pulmonary embolism (PE), atrial fibrillation, valve replacement, and coronary occlusion.
• Daily dosing (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 the inhibition of prostaglandin production.
• Antithrombotic indications: Reduce 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; must undergo a two-step hepatic conversion.
• Platelet aggregation inhibitor.
• Indications: History of MI, stroke, PAD, and acute coronary syndrome (ACS).
• Slightly more effective than aspirin (except for stroke prophylaxis).
• Metabolized by the liver.
• Steady state in 3 to 7 days.
• 75 mg QD (plus aspirin); 300-mg loading dose for ACS.
• Ticlopidine:
• Platelet aggregation inhibitor.
• Indicated for stroke.
• More effective than aspirin.
• Steady state in 14–21 days.
• Metabolized by the liver.
• Risk of life-threatening blood dyscrasias.
• Use only if aspirin and clopidogrel are unacceptable.
• Prasurgel:
• A prodrug.
• Only indicated in use for prevention of thrombosis in patients with ACS undergoing percutaneous coronary intervention.
• In combination with aspirin decreases nonfatal MI but has 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.
• 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 bleeding.