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.
• Arterial Blood Pressure: Product of systemic vascular resistance and cardiac output (heart rate × stroke volume).
• Cardiovascular Disease (CVD): Damage to the heart, blood vessels, or circulation.
• Chronotropic: Influencing the rate of heartbeat.
• Circadian Rhythm: Human biologic variations within a 24-hour cycle.
• Creatinine Clearance (CrCl): Measurement of renal clearance of creatinine, estimating glomerular filtration rate (GFR).
• D-dimers: Degradation fragments of cross-linked fibrin, indicating fibrinolysis.
• Dose-Ceiling Effect: Maximum drug dose beyond which therapeutic effect plateaus, but toxic effects increase.
• Fibrin Split or Fibrinogen Degradation Products (FDPs): Peptides resulting from plasmin action on fibrinogen and fibrin, acting as anticoagulants.
• Glomerular Filtration Rate (GFR): Volume of water filtered by the kidney; equivalent to insulin clearance.
• Hypertensive Emergency: Blood pressure above 180/120 mmHg with acute target organ injury. Requires ICU admission and BP monitoring.
• Hypertensive Urgency: Blood pressure above 180/120 mmHg without acute target organ complications; control over 24-48 hours.
• Inotropes: Drugs influencing heart muscle contractility.
• Intrinsic Sympathomimetic Activity (ISA): Ability to activate and block adrenergic receptors, producing a net stimulatory effect.
• Renin: Enzyme released by the kidney that converts angiotensinogen into angiotensin I.

Hypertension

• High blood pressure is defined as ≥140/90 mmHg.
• Primary hypertension has an unknown etiology.
• Secondary hypertension is due to a known disease process.
• Adversely affects the heart, brain, kidney, and eye (CVD).
• Diagnosis requires two or more seated BP readings taken on different days.
• Increases risk of LV hypertrophy, angina, MI, heart failure, stroke, PAD, retinopathy, and renal failure.

Pathophysiology of Hypertension

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

Hypertensive Crisis

• Blood pressure is > 180/120 mmHg.
• Hypertensive urgency presents without signs/symptoms of organ complications.
• Hypertensive emergency involves acute, chronic, or progressive organ injury.

Hypertension Pharmacotherapy

• First-line agents include ACEIs, ARBs, CCBs, beta-blockers, and thiazide-type diuretics.
• Second-line agents include vasodilators, alpha-blockers, alpha2-agonists, and antiadrenergics.

Angiotensin-Converting Enzyme Inhibitors (ACEIs)

• Suppress the renin–angiotensin–aldosterone system by blocking the conversion of angiotensin I to angiotensin II.
• Reduce peripheral arterial resistance (PAR), increase CO, and increase renal blood flow.
• Indicated for HTN, heart failure, systolic dysfunction, MI prevention, LV dysfunction, and diabetic neuropathy.
• Effective alone or with thiazide-type diuretics; generally decrease SBP and DBP 15–25%.
• Dry cough is the most common side effect.
• Do not induce glucose intolerance, hyperlipidemia, or hyperuricemia.
• Significant interaction with NSAIDs.

Angiotensin II Receptor Blockers (ARBs)

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

Direct Renin Inhibitors (DRI)

• Act by inhibiting renin.
• Aliskiren is the only DRI available.
• Side effects include 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.
• Amlodipine, felodipine, isradipine, nifedipine, and nisoldipine have negligible chronotropic effects.
• Only sustained-release dosage forms of nifedipine are indicated for hypertension.

Beta-Blockers

• Block beta-receptors on renal juxtaglomerular cells and myocardial beta-receptors.
• Indicated for HTN, angina pectoris, cardiac dysrhythmias, MI prevention, and chronic heart failure.
• May induce bronchospasm and render beta-agonists ineffective.

Aldosterone Antagonists

• Spironolactone is a weak diuretic used with other antihypertensives.
• Eplerenone is indicated for HTN and post-MI heart failure with minimal adverse sexual side effects.

Centrally Acting Adrenergic Agents

• Alpha2-agonists affect CO and peripheral resistance.
• Negative inotrope/negative chronotrope.
• Clonidine transdermal is the most effective and least toxic.

Alpha1-Adrenergic Antagonists

• Selectively block postsynaptic alpha1-receptors.
• Cause arterial and venous dilation, decreasing preload and afterload.
• The first dose can cause 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.
• Guanethidine and guanadrel substitute neurotransmitters.

Vasodilators

• Hydralazine and minoxidil are second-line treatments 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 beta-blocker and loop diuretic.

Angina

• Symptom of myocardial ischemia due to an imbalance of myocardial O2 supply and demand.
• May present as heavy chest pressure, burning sensation, SOB, or pain over the sternum, left shoulder, or lower jaw.

Pharmacotherapy for Angina

• Nitrates reduce myocardial oxygen demand by dilating coronary arteries and collaterals.
• Indications include angina, acute MI, and HTN.
• Common adverse reactions include tachycardia, palpitations, hypotension, dizziness, flushing, and headache.
• Nitroglycerin sublingual should be administered every 5 minutes × 3.
• Ranolazine is indicated for chronic angina not responding to other medications.

Antithrombotic Agents

• Prevent or break up blood clots.
• Formation is initiated by injury to the endothelium.
• Platelets release chemicals that cause further aggregation, forming an unstable thrombus.
• The fibrinolytic system removes insoluble fibrin clots.

Three Categories of Antithrombotic Agents

• Anticoagulants
• Antiplatelets
• Thrombolytics

Anticoagulant Agents

• Heparins (unfractionated heparin and low-molecular-weight heparin): Indicated for venous thromboembolism and atrial fibrillation.
• Side effects include bleeding, thrombocytopenia, and hyperkalemia.
• Protamine sulfate is the antidote for heparin.
• Direct thrombin inhibitors include desirudin, bivalirudin, argatroban, and lepirudin. Hemorrhage is a common side effect.
• Warfarin is an oral anticoagulant for venous thrombosis, pulmonary embolism and atrial fibrillation, with a delayed onset of 3–5 days.

Antiplatelet Agents

• Aspirin reduces platelet aggregation by inhibiting prostaglandin production.
• Dipyridamole is a vasodilator and platelet adhesion inhibitor.
• Clopidogrel is a prodrug that inhibits platelet aggregation and is used for a history of MI, stroke, PAD, and acute coronary syndrome (ACS).
• Ticlopidine inhibits platelet aggregation.
• Prasurgel is only indicated in use for prevention of thrombosis in patients with ACS undergoing percutaneous coronary intervention.
• Cilostazol and pentoxifylline cause vasodilation and inhibition of platelet aggregation, indicated for PAD pain.
• Glycoprotein IIb/IIIa inhibitors are indicated for ACS.

Thrombolytic Agents

• Indicated for PE, ischemic stroke, and acute ST-segment elevation MI.
• 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 include internal bleeding, aortic dissection, head injury, or recent stroke.
• Bleeding is the most common adverse effect.