Antihypertensives and Circulation

• Chapter focuses on drugs affecting circulation, specifically antihypertensives, antianginals, and antithrombotics

Term

• Antithrombotics Drugs: that prevent or break up blood clots in such conditions as thrombosis or embolism; antithrombotics include anticoagulants, antiplatelets, and thrombolytics.
• Arterial blood pressure (blood pressure): Defined hemodynamically as the product of systemic vascular resistance and cardiac output (heart rate × stroke volume).
• Cardiovascular disease (CVD) : Damage to the heart and the blood vessels or circulation, including damage to the brain, kidney, and the eyes.
• Chronotropic : Influencing the rate of rhythmic movements (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; approximates glomerular filtration rate (GFR) but overestimates GFR by 10% to 15%; used for drug dosage guidelines.
• D-dimers : Covalently cross-linked degradation fragments of the cross-linked fibrin polymer during plasmin-mediated fibrinolysis; level increases after the onset of fibrinolysis and allows for identification of the presence of fibrinolysis.
• Dose-ceiling : effect Maximum dose of a drug, beyond which it no longer exerts a therapeutic effect; however, its toxic effect increases.
• Fibrin split or fibrinogen degradation products (FDPs) : Small peptides that result after the action of plasmin on fibrinogen and fibrin in the fibrinolytic process. FDPs are anticoagulant substances that can cause bleeding if fibrinolysis becomes uncontrolled and excessive.
• Glomerular filtration rate (GFR) : Volume of water filtered from the plasma by the kidney via the glomerular capillary walls into Bowman capsules per unit of time; considered to be 90% of creatinine clearance and equivalent to insulin clearance.
• Hypertensive emergency : Blood pressure greater than 180/120 mm Hg, with the elevation of blood pressure accompanied by acute, progressing target organ injury.
• Hypertensive urgency : Blood pressure greater than 180/120 mm Hg without signs or symptoms of acute target organ complications.
• Inotropes : Drugs influencing the contractility of a muscle (heart).
• Intrinsic sympathomimetic activity (ISA) : Having the ability to activate and block adrenergic receptors, producing a net stimulatory effect on the sympathetic nervous system.
• Renin Enzyme: also known as angiotensinogenase, released by the kidney in response to lack of renal blood flow and responsible for converting angiotensinogen into angiotensin

Epidemiology and Etiology of Hypertension

• High blood pressure is defined as ≥140/90 mmHg.
• Primary hypertension has unknown etiology and is termed essential hypertension.
• Secondary hypertension results from a known disease process.
• Hypertension adversely affects organs like the heart, brain, kidney, and eye.
• These adverse effects are termed cardiovascular disease (CVD).
• Hypertension is diagnosed via two or more seated blood pressure readings taken on different days.
• Hypertension increases the risk of conditions such as 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 a major factor in systolic blood pressure (SBP), which affects venous capacitance.
• Afterload is the major factor in diastolic blood pressure (DBP).

Hypertensive Crisis

• Hypertensive crisis happens when a patient has blood pressure > 180/120 mmHg.
• Hypertensive urgency involves no signs or symptoms of organ complication and control can be done over a period of 24-48 hours.
• Hypertensive urgency can present with severe headaches, shortness of breath (SOB), nose bleeds, and severe anxiety.
• Hypertensive emergency involves acute, chronic, or progressive organ injury and requires admission to an ICU and BP 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)

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

Angiotensin II Receptor Blockers (ARBs)

• Receptors for ARBs are found in vascular smooth muscle, myocardium, brain, kidney, liver, uterus, and adrenal glands.
• ARBs are indicated for HTN and treatment of heart failure.
• ARBs are slightly "weaker" than ACEIs.
• Side effects of ARBs:
  • Orthostatic hypotension
  • Hyperkalemia
  • Neutropenia
  • Nephrotoxicity
  • Fetotoxicity

Direct Renin Inhibitors (DRI)

• DRIs act by inhibiting renin.
• DRIs can be used alone or in combination with other antihypertensive agents.
• Aliskiren is the only DRI available.
• Side effects of DRIs:
  • Diarrhea
  • Headache
  • Dizziness
  • Fatigue
  • Upper respiratory track infection
  • Nasopharyngitis
  • Back pain

Calcium Channel Blockers (CCBs)

• CCBs cause coronary and peripheral vasodilation via L-channel blockade.
• Verapamil and diltiazem:
  • Have negative chronotropic and inotropic effects
  • Have long-acting formulations that target circadian rhythm
  • Have a high incidence of constipation

CCBs - Amlodipine, Felodipine, Isradipine, Nifedipine, Nisoldipine

• Have negligible chronotropic effects (except nifedipine).
• Only sustained-release dosage forms of nifedipine are indicated for hypertension.
• Amlodipine and felodipine can be used in patients with heart failure.

Beta-Blockers

• Beta-Blockers MOA includes blockade of the β-receptors on the renal juxtaglomerular cells, blockade of myocardial β-receptors and blockade of central nervous system β-receptors.
• Beta-Blockers are indicated for HTN, angina pectoris, cardiac dysrhythmias, MI prevention, chronic heart failure, and pheochromocytoma.
• Beta-Blockers indications also include migraine prophylaxis and alcohol withdrawal.
• Beta-Blockers may induce bronchospasm and render β-agonist ineffective.

Diuretics

• Five classes: Thiazide and thiazide-like agents, loop diuretics, K-sparing agents, carbonic anhydrase inhibitors (CAIs), and osmotics.
• K-sparing agents can be used for HTN
• Interact with NSAIDs.

Potassium-Sparing Diuretics

• Potassium-Sparing Diuretics are weak if used alone.
• Potassium-Sparing Diuretics have have an Additive effect with thiazides
• Amiloride (Midamor) and triamterene (Dyrenium) are Potassium-Sparing Diuretics
• Side effects of Potassium-Sparing Diuretics include dyspepsia, cramps, nausea, diarrhea, mental confusion, lethargy, headache, dizziness, and leg cramps.

Thiazide and Thiazide-Like Diuretics

• Thiazide and Thiazide-Like Diuretics increase Na+ and Cl- excretion
• Thiazide and Thiazide-Like Diuretics are Indicated for hypertension, chronic edema, chronic heart failure, and ascites
• Thiazide and Thiazide-Like Diuretics has a Dose-ceiling effect
• It can take 2 to 4 weeks for Thiazide and Thiazide-Like Diuretics to elicit full effect
• Side effects of Thiazide and Thiazide-Like Diuretics include hypokalemia, hypocalcemia, hyperuricemia, hyperglycemia, hyperlipidemia, and sexual dysfunction

Loop Diuretics

• Loop Diuretics decrease Na+ reabsorption at the ascending limb of the loop of Henle
• Loop Diuretics are Indicated for chronic heart failure, ascites, renal failure, pulmonary edema, hypercalcemia, hypermagnesemia, and syndrome of inappropriate antidiuretic hormone
• Loop Diuretics are a Second-line treatment for management of HTN
• Side effects of Loop Diuretics include frequent urination
• Side effects of Loop Diuretics may cause hyperglycemia, hyperuricemia, dyspepsia, photosensitivity, and ototoxicity

Aldosterone Antagonists

• Aldosterone Antagonists include Spironolactone (Aldactone) and eplerenone (Inspra)
• Spironolactone is a weak diuretic, often used with other antihypertensives
  • Spironolactone is indicated for hepatic cirrhosis, primary hyperaldosteronism, hypokalemia, heart failure, and when used in combination for HTN
  • Spironolactone can have adverse effects such as impotence, gynecomastia, deep voice, menstrual irregularities, hirsutism, gastrointestinal upset, rash, and drowsiness

Alpha 2 - Agonists

• Alpha 2 - Agonists Affect CO and peripheral resistance
• Alpha 2 - Agonists has a Negative inotrope/negative chronotrope effects Alpha 2 - Agonists are effective, but riddled with side effects:
• High incidence of anticholinergic-like effects
• Clonidine transdermal is the most effective and least toxic

α1-Adrenergic Antagonists

• α1-Adrenergic Antagonists selectively block postsynaptic α1-receptors
• α1-Adrenergic Antagonists cause arterial and venous dilation leading to a decrease in preload and afterload Manifests with orthostatic hypotension, tachycardia, palpitations, dizziness, headaches, and syncope along with Initial doses should be low and at bedtime

Antiadrenergic Agents

• Antiadrenergic Agents are are second-line drugs
• Reserpine
  • Reserpine depletes postganglionic norepinephrine
  • Reserpine May cause: Sedation, depression, psychosis, peptic ulcers, nasal stuffiness
• Guanethidine (Ismelin) and guanadrel (Hylorel)
  • Guanethidine (Ismelin) and guanadrel (Hylorel) substitute neurotransmitters
  • Guanethidine (Ismelin) and guanadrel (Hylorel) May cause orthostatic hypotension, sexual dysfunction, explosive diarrhea
  • The Antihypertensive effects of Guanethidine (Ismelin) and guanadrel (Hylorel) are diminished when combined with tricyclic antidepressants, amphetamines, and 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, increased CO • Often given with a β-blocker and loop diuretic

Epidemiology, Etiology, and Pathophysiology of Angina

• "Chest pain” that is caused by imbalances to miocardial O2 supply and/or demand
• Symptom of myocardial ischemia
• May present as: Heavy weight or pressure on the chest, burning sensation, shortness of breath (SOB), or pain over sternum, left shoulder, or lower jaw

Pharmacotherapy for Angina

• Nitrates
  • Nitroglycerin reduces myocardial oxygen demand by dilating coronary arteries and collaterals (mostly venous effect)
  • Indicated in patients with Angina, acute MI, or HTN
  • Administer via: Oral, IV, ointment, transdermal, translingual, or sublingual routes
  • Sublingual administration: Q 5 minutes and repeat × 3, then seek care
  • Adverse reactions: Tachycardia, palpitations, hypotension, dizziness, flushing, and headache

Pharmacotherapy for Angina

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)
• has Adverse reactions of dizziness, palpitations, headache, constipation, nausea, pain, and peripheral edema
• Contraindicated in hepatic dysfunction

Antithrombotic Agents

• Agents that prevent or break up blood clots
• Formation and elimination of acute coronary thrombus occurs following:
  • Formation that is initiated by injury to the endothelium
  • Platelets adhere to site of injury, release chemicals that cause further aggregation, forming an unstable thrombus
  • Eventually an insoluble fibrin clot forms and must be removed by fibrinolytic system for homeostasis to be maintained

Antithrombotic Agents

• Three categories: Anticoagulants, antiplatelets, and thrombolytics

Anticoagulant Agents: Heparins

Including: Unfractionated heparin and low-molecular-weight heparin

• Heparins are Indicated for venous thromboembolism, pulmonary embolism, atrial fibrillation (AF), disseminated intravascular coagulation (DIC), and peripheral arterial embolism
• Heparins are extracted from porcine intestinal mucosa whose overall treatment goal is to balance unwanted clotting with risk of hemorrhage
• Side effects include: Bleeding, thrombocytopenia, hyperkalemia, osteoporosis, and increased liver enzyme tests (LETs)
• Antidote is: Protamine sulfate

Direct thrombin inhibitors

• Desirudin (Iprivask): Used in patients following deep vein thrombosis (DVT)
• Bivalirudin (Angiomax): Used in patients with unstable angina
• Argatroban and lepirudin (Refludan): Used for anticoagulation of patients with heparin-induced thrombocytopenia type 2 (HIT-2)
• Common adverse side effect is: Hemorrhage

Anticoagulant Agents - Warfarin

• Oral anticoagulant for venous thrombosis, pulmonary embolism (PE), atrial fibrillation, valve replacement, and coronary occlusion that is given via Daily dosing (delayed onset of 3–5 days)
• Dosing is adjusted until reaching target International normalized ratio (INR) which is then the standard for monitoring therapy
• Common Averse side effect is Hemorrhage that can increase/decrease with diet, disease states, and drugs

Aspirin

• Aspirin is a prostaglandin derivative that decreases thromboxane A2
• it Reduces platelet aggregation by the inhibition prostaglandin production
• Is Antithrombotic and Used to reduce risk of thrombosis, transient ischemic attack (TIA), or stroke
• Averse side effects : Peptic ulcer, renal dysfunction, HTN, tinnitus, pulmonary dysfunction, and bleeding
• Caution: Ibuprofen inhibits pharmacological effect; concurrent NSAID use may cause fatal gastropathy

Dipyridamole

• Dipyridamole is a Vasodilator and platelet adhesion inhibitor that is Indicated only as an adjunct to warfarin in the prevention of postoperative thromboembolic complications of cardiac valve replacement
• Dipyridamole may potentiate the effect of adenosine
• Patients may experience Adverse reactions such as: Headache, dizziness, hypotension, and distress

Clopidogrel (Plavix)

• Clopidogrel (Plavix) is a Prodrug that must undergo a two-step hepatic conversion
• Is a platelet aggregation inhibitor
• Is indicated in patients whom had a History of MI, stroke, PAD, or acute coronary syndrome (ACS)
• Slightly more effective than aspirin (except for stroke prophylaxis)
• Metabolized by the liver and reaches Steady state in 3 to 7 days when administering 75 mg QD (plus aspirin)
• A 300-mg loading dose for ACS is often given

Ticlopidine

• Ticlopidine is a Platelet aggregation inhibitor and indicated in patients whom had a storke
• Ticlopidine steady state in 14–21 days
• and is Metabolized by the liver
• The risk of life-threatening blood dyscrasias are what makes it Usable only in patients whom aspirin and clopidogrel are unacceptable

Prasurgel

• Prasurgel is a prodrug that is Only Indicated if you are attempting to prevent 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
• Common Averse reaction: Bleeding

Cilostazol and pentoxifylline

• Cilostazol and pentoxifylline cause vasodilation and inhibition of platelet aggregation, indicated for PAD pain
• Patients can benefit from clinical use after up to 12 weeks
• However there are Transient adverse with effects: Headache, diarrhea, dizziness, and palpitations
• dosage : 100 mg BID on an empty stomach

Glycoprotein IIb/IIIa inhibitors

• Glycoprotein IIb/IIIa inhibitors are indicated for ACS.
• Abciximab (ReoPro) is the "drug of choice.”
• Glycoprotein IIb/IIIa inhibitors are not available in oral formulation (ineffective).
• Averse side effect: Bleeding

Thrombolytic Agents

• Indicated for PE, ischemic stroke, and acute ST segment elevation MI
• Common Agents include: Streptokinase (second line), alteplase, reteplase, and tenecteplase
• Thrombolytic 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.
• Thrombolytic Agents have Internal bleeding, aortic dissection as a contraindication, head injury or stroke in the last 3 months, HTN, or if patent is actively using an anticoagulant
• The most common adverse effect that patients face is Bleeding