Drugs affecting circulation & CVD

• Drugs affecting circulation include antihypertensives, antianginals, and antithrombotics
• Cardiovascular disease (CVD) is damage to the heart, blood vessels, or overall circulation

Key Terms

• Antithrombotics: Drugs preventing or breaking up blood clots in conditions like thrombosis or embolism, including anticoagulants, antiplatelets, and thrombolytics.
• Arterial Blood Pressure: Hemodynamically defined as the product of systemic vascular resistance and cardiac output (heart rate × stroke volume).
• Chronotropic: Influencing the rate of rhythmic movements, especially 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).
• D-dimers: Degradation fragments of cross-linked fibrin polymer during fibrinolysis, indicating the presence of fibrinolysis.
• Dose-ceiling effect: Maximum drug dose beyond which therapeutic effect doesn't increase, but toxic effects do.
• Fibrin Split or Fibrinogen Degradation Products (FDPs): Peptides resulting from plasmin's action on fibrinogen and fibrin, acting as anticoagulants and potentially causing bleeding if fibrinolysis is excessive.
• Glomerular Filtration Rate (GFR): Volume of water filtered by the kidney from plasma into Bowman capsules per unit of time.
• Hypertensive Emergency: Blood pressure exceeding 180/120 mm Hg with acute, progressing target organ injury.
• Hypertensive Urgency: Blood pressure exceeding 180/120 mm Hg without acute target organ complication signs or symptoms.
• Inotropes: Drugs affecting muscle contractility, particularly in the heart.
• Intrinsic Sympathomimetic Activity (ISA): Ability to activate and block adrenergic receptors, resulting in a net stimulatory effect on the sympathetic nervous system.
• Renin: Enzyme released by the kidney to convert angiotensinogen into angiotensin I in response to reduced renal blood flow.

Epidemiology and Etiology of Hypertension

• High blood pressure is defined as ≥140/90 mm Hg.
• Primary hypertension has an unknown cause (essential hypertension).
• Secondary hypertension results from a known disease process.
• Hypertension can adversely affect the heart, brain, kidneys, and eyes, leading to cardiovascular disease (CVD).
• Diagnosis involves two or more seated blood pressure readings taken on different days.
• Hypertension increases the risk of left ventricular hypertrophy, angina, myocardial infarction, heart failure, stroke, peripheral arterial disease, 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 influencing systolic blood pressure (SBP) and affects venous capacitance.
• Afterload is a major factor influencing diastolic blood pressure (DBP).

Hypertensive Crisis

• Defined as blood pressure > 180/120 mmHg.
• Hypertensive urgency involves no signs/symptoms of organ complication, possibly with severe headaches, shortness of breath, nosebleeds, or severe anxiety, and is managed 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 include:
  • Angiotensin-converting enzyme inhibitors (ACEIs)
  • Angiotensin II receptor blockers (ARBs)
  • Calcium channel blockers (CCBs)
  • β-Blockers
  • Thiazide-type diuretics
• Second-line agents include:
  • Vasodilators
  • α-Blockers
  • α2-Agonists
  • Antiadrenergics

Angiotensin-Converting Enzyme Inhibitors (ACEIs)

• Suppress the renin-angiotensin-aldosterone system by blocking the conversion of angiotensin I to angiotensin II.
• Hemodynamic effects include reduced peripheral arterial resistance, increased cardiac output, and increased renal blood flow.
• ACEIs are indicated for hypertension, heart failure, systolic dysfunction, MI prevention, LV dysfunction, and diabetic neuropathy.
• They are effective alone or with thiazide-type diuretics and generally decrease SBP and DBP by 15–25%.
• A common side effect is a dry cough, with rare occurrences of angioedema.
• ACEIs do not induce glucose intolerance, hyperlipidemia, or hyperuricemia.
• There is a significant interaction with nonsteroidal anti-inflammatory drugs (NSAIDs).

Angiotensin II Receptor Blockers (ARBs)

• Receptors are found in vascular smooth muscle, myocardium, brain, kidney, liver, uterus, and adrenal glands.
• ARBs are indicated for hypertension and heart failure treatment.
• They are considered slightly "weaker" than ACEIs.
• Side effects include 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 include diarrhea, headache, dizziness, fatigue, upper respiratory tract 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, are formulated for long-acting circadian rhythm targeting, and have a high incidence of constipation.
• 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 and central nervous system β-receptors.
• Indications include hypertension, 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-agonists 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, and heart failure, and used in combination for HTN.
  • Adverse effects of spironolactone include impotence, gynecomastia, deep voice, menstrual irregularities, hirsutism, gastrointestinal upset, rash, and drowsiness.
• Eplerenone is indicated for HTN and post-MI heart failure.
  • It has minimal adverse sexual side effects but a higher risk of hyperkalemia.

Centrally Acting Adrenergic Agents (α2-Agonists)

• Affect cardiac output and peripheral resistance with negative inotropic and chronotropic effects.
• α2-Agonists are effective but have side effects, including a high incidence of anticholinergic-like effects.
• Clonidine transdermal is the most effective and least toxic.

α1-Adrenergic Antagonists

• Selectively block postsynaptic α1-receptors, causing arterial and venous dilation, decreasing preload and afterload.
• The first-dose phenomenon manifests with orthostatic hypotension, tachycardia, palpitations, dizziness, headaches, and syncope.
  • Initial doses should be low and taken at bedtime.
• Indications include HTN, benign prostatic hyperplasia, heart failure, and Raynaud’s vasospasm.

Antiadrenergic Agents

• Second-line drugs.
• Reserpine depletes postganglionic norepinephrine and 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 cardiac output.
• Often given with a β-blocker and loop diuretic.

Epidemiology, Etiology, and Pathophysiology of Angina

• Angina is "chest pain" resulting from myocardial ischemia, where there is an imbalance of myocardial oxygen supply and demand.
• It may present as a heavy weight or pressure on the chest, burning sensation, shortness of breath, or pain over the sternum, left shoulder, or lower jaw.

Pharmacotherapy for Angina

• Nitrates (e.g., nitroglycerin) reduce myocardial oxygen demand by dilating coronary arteries and collaterals (mostly venous effect).
  • Indications include angina, acute MI, and HTN.
  • Formulations include oral, IV, ointment, transdermal, translingual, and sublingual.
  • For sublingual administration, administer 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: Formation is initiated by injury to the endothelium.
  • Platelets adhere to the injury site, release chemicals causing further aggregation, forming an unstable thrombus.
  • An insoluble fibrin clot eventually forms.
  • The fibrinolytic system must remove it for homeostasis to be maintained.
• Three categories:
  • Anticoagulants
  • Antiplatelets
  • Thrombolytics

Anticoagulant Agents

• Heparins: Unfractionated heparin and low-molecular-weight heparin.
  • Indicated for venous thromboembolism, pulmonary embolism, atrial fibrillation, 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) is indicated for deep vein thrombosis (DVT).
• Bivalirudin (Angiomax) is indicated for unstable angina.
• Argatroban and lepirudin (Refludan) are 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: Prostaglandin derivative thromboxane A2 induces 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 preventing 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; Steady state in 3 to 7 days.
• Dosage: 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 for the prevention of thrombosis in patients with ACS undergoing percutaneous coronary intervention.
• In combination with aspirin, it 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, 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, acute ST-segment elevation MI.
• Agents: Streptokinase (second line), alteplase, reteplase, and tenecteplase.
  • Therapy should begin within 12 hours of symptoms.
  • Thrombolytics are preferred over 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, anticoagulant use.
• Bleeding is the most common adverse effect, including gastrointestinal, genitourinary, respiratory tract, retroperitoneal, and intracranial bleeding.