Drugs_Directly_Acting_on_the_Vasculature.V2 (3).pdf

11/2/23, 2:19 PM Drugs_Directly_Acting_on_the_Vasculature.V2 (3) Drugs_Directly_Acting_on_the_Vasculature.V2 (3) Page 4: Calcium Channel Blockers (CCBs): MOA: Bind to the L-type calcium channel in cardiac and smooth muscle and inhibit calcium influx Effects on cardiac muscle: Decrease cardiac co...

11/2/23, 2:19 PM Drugs_Directly_Acting_on_the_Vasculature.V2 (3) Drugs_Directly_Acting_on_the_Vasculature.V2 (3) Page 4: Calcium Channel Blockers (CCBs): MOA: Bind to the L-type calcium channel in cardiac and smooth muscle and inhibit calcium influx Effects on cardiac muscle: Decrease cardiac contractility (negative inotropic effect) Decrease SA node automaticity (negative chronotropic effect) Decrease AV node conduction (negative dromotropic effect) Effects on smooth muscle: Relaxation and vasodilation Decrease peripheral vascular resistance (PVR) Page 5: Calcium Channel Blockers (CCBs): Dihydropyridines: Nifedipine Amlodipine Clevidipine Felodipine Isradipine Nicardipine Nimodipine Nisoldipine Non-dihydropyridines: Verapamil Diltiazem Page 6: CCBs: Pharmacology Non-dihydropyridines: Decrease heart rate Slow AV conduction Negative inotropic effect Dihydropyridines: May cause a baroreceptor-mediated tachycardia due to potent peripheral vasodilation Do not alter conduction through the AV node Page 7: CCBs: Pharmacology Vascular smooth muscle is more sensitive to CCBs than bronchiolar, GI, and uterine smooth muscle Arterial smooth muscle is more sensitive to CCBs than venous smooth muscle Action on smooth muscle: DHPs > verapamil > diltiazem Action on SA and AV node: Verapamil > diltiazem > DHPs https://knowt.com/note/f31f5674-0271-4ee2-bab1-d0f32eecd3cb/DrugsDirectlyActingontheVasculatureV2-3 1/6 11/2/23, 2:19 PM Page 8: Drugs_Directly_Acting_on_the_Vasculature.V2 (3) CCBs: Pharmacokinetics All oral CCBs come in long-acting products Nifedipine, verapamil, diltiazem, and nicardipine are available in oral and IV formulation Amlodipine does not require an extended-release product for once daily dosing Page 9: CCBs: Adverse Effects/Contraindications Non-dihydropyridines: AEs: Bradycardia, Constipation Dihydropyridines: AEs: Peripheral edema (dose-dependent, usually bilateral, not caused by fluid overload), Gingival hyperplasia, Reflex tachycardia, Gastroesophageal reflux disease Page 10: CCBs: Drug Interactions All are 3A4 substrates; inhibitors of 3A4 may increase concentrations and lead to toxicity Non-DHPs are also 3A4 inhibitors and may increase concentrations of other drugs such as simvastatin, alprazolam, cyclosporine Non-DHPs are also P-gp substrates and inhibitors; verapamil increases serum digoxin levels 50-75% Inhibition of renal clearance and extrarenal clearance Additive effects, i.e., bradycardia with beta-blockers, hypotension with other antihypertensive drugs Page 11: Other Vasodilators: Hydralazine Minoxidil Nitroprusside Fenoldopam Mechanism of Action: Potentiate cyclic guanosine monophosphate (cGMP) activity Release nitric oxide from drug or endothelium Hyperpolarization of smooth muscle membranes by opening potassium channels Activation of dopamine receptors Page 12: Hydralazine: Pharmacology MOA: unclear; possibly inhibits release of Ca2+ in arteries, may stimulate NO release Potent arteriolar vasodilator à reflex tachycardia Often coadministered with beta-blockers to prevent reflex tachycardia Page 13: Hydralazine: Pharmacokinetics Metabolized hepatically via acetylation; slow acetylators have higher blood levels and pharmacological effects t1/2 ~ 1.5 - 3 h but vascular effects persist longer Dosing: 3 times daily Drug interactions: Additive hypotensive effects with other drugs Precaution: Patients with ischemic heart disease; reflex tachycardia can provoke angina and ischemic arrhythmias https://knowt.com/note/f31f5674-0271-4ee2-bab1-d0f32eecd3cb/DrugsDirectlyActingontheVasculatureV2-3 2/6 11/2/23, 2:19 PM Page 14: Drugs_Directly_Acting_on_the_Vasculature.V2 (3) Hydralazine: Adverse Effects Tachycardia Peripheral edema Systemic Lupus Erythematosus (SLE) - 10-20% with high doses (~400mg/day) and slow acetylators Lupus-like syndrome: arthralgia, myalgia, skin rash & fever Page 15: Minoxidil: MOA K+ ATP channel opener; hyperpolarizes vascular smooth muscle cells, thereby attenuating the cellular response to depolarizing stimuli Powerful arteriolar vasodilator Peripheral edema and reflex tachycardia are common Co-prescribe beta-blocker and loop diuretic to counteract these effects Page 16: Minoxidil: Adverse Effects Headache Sweating Tachycardia Peripheral edema Hypertrichosis Drug interactions: Additive hypotensive effects with other drugs Page 17: Fenoldopam: MOA Agonist at dopamine D1 receptor à dilates arterioles in systemic vascular beds (coronary, renal, mesenteric vessels) Administered IV drip for severe HTN Rapidly converted to inactive glucuronide, conjugates t1/2 ~ 5-10 minutes Adverse effects: Reflex tachycardia, headache, flushing, and hypokalemia Page 21: Nitric Oxide (NO) Donors Nitroprusside Organic nitrates (Nitroglycerin, Isosorbide dinitrate, Isosorbide mononitrate) Organic nitrite (Amyl nitrite) Page 20: NO Donors: MOA Biotransformation liberates NO, activates guanylyl cyclase, increases cyclic guanosine monophosphate (cGMP) formation, activates cGMP-dependent protein kinase (PKG), PKG phosphorylates myosin lightchain phosphatase (MLCP), MLCP dephosphorylates myosin light-chain phosphate, muscle relaxation à vasodilation Page 21: Nitroprusside: Pharmacology Mechanism of NO release is unclear; may involve both enzymatic and nonenzymatic pathways https://knowt.com/note/f31f5674-0271-4ee2-bab1-d0f32eecd3cb/DrugsDirectlyActingontheVasculatureV2-3 3/6 11/2/23, 2:19 PM Drugs_Directly_Acting_on_the_Vasculature.V2 (3) Non-selective vasodilator; dilates both arterial and venous vessels Do NOT develop tolerance to nitroprusside unlike nitroglycerin Unlike hydralazine and minoxidil, only a modest increase in heart rate occurs with a net decrease in myocardial oxygen consumption Page 22: Nitroprusside: Pharmacokinetics Complex Page 23: Nitroprusside: Indication and Toxicity Toxicity of Nitroprusside: Thiocyanate accumulation Symptoms of toxicity: Weakness Disorientation Psychosis Muscle spasms Convulsions Page 24: Organic Nitrates and Drug Nitrites Short-acting Nitroglycerin: Glyceryl trinitrate (Nitroglycerin), sublingual Isosorbide dinitrate, sublingual Long-acting Nitroglycerin: Nitroglycerin, oral sustained-action Nitroglycerin, 2% ointment, transdermal Nitroglycerin, slow-release, buccal Nitroglycerin, slow-release patch, transdermal Isosorbide dinitrate, sublingual Isosorbide dinitrate, oral Isosorbide dinitrate, chewable oral Isosorbide mononitrate, oral Page 25: Nitrates: Onset and Duration of Action Onset and Duration of Action of Nitrates: Nitroglycerin: Short-acting Sublingual: Onset 2 min, Duration 10-30 minutes Spray: Onset 2 min, Duration 25 min Isosorbide dinitrate, sublingual: Onset 10-60 minutes, Duration 35 min Amyl nitrite, inhalant: Onset 3-5 minutes, Duration 4-8 hrs Nitroglycerin, oral sustained-action: Onset 30 min, Duration 6-8 hours Nitroglycerin, 2% ointment, transdermal: Onset 3-6 hours, Duration 3-6 hours Nitroglycerin, slow-release, buccal: Onset 5 min, Duration 30 min Nitroglycerin, slow-release patch, transdermal: Onset 8-10 hours, Duration 8-10 hours Isosorbide dinitrate, sublingual: Onset 1 hr, Duration 1.5-2 hours Isosorbide dinitrate, oral: Onset 30 min, Duration 4-6 hours Isosorbide dinitrate, chewable oral: Onset 2-3 hours, Duration 8 hrs Isosorbide mononitrate, oral: Onset 6-10 hours, Duration 12 hrs Page 26: Nitroglycerin: Pharmacology Pharmacology of Nitroglycerin: https://knowt.com/note/f31f5674-0271-4ee2-bab1-d0f32eecd3cb/DrugsDirectlyActingontheVasculatureV2-3 4/6 11/2/23, 2:19 PM Drugs_Directly_Acting_on_the_Vasculature.V2 (3) Nitroglycerin half-life (t1/2): ~2-8 minutes Requires enzymatic activity to release NO (unlike nitroprusside) Denitrated by: Glutathione S-transferase Aldehyde dehydrogenase isoform 2 (ALDH2) Most important enzyme for nitroglycerin activation Metabolized (denitrated) products have a half-life of ~3 hours Metabolite (1,2-dinitroglycerin) provides most of the vasodilator activity Page 27: Nitrates: Clinical Use Mechanism of clinical effects of Nitrates: Preferentially relaxes venous smooth muscle Increases venous capacitance Reduces preload (decreasing myocardial oxygen consumption) Page 28: Nitrates: AEs and DIs Adverse Effects (AEs) of Nitrates: Excessive vasodilation: Throbbing headache Hypotension Dizziness Reflex tachycardia Remove patches before use of external defibrillators to prevent superficial burns Drug Interactions (DIs) of Nitrates: Sildenafil (Viagra) may interact to cause serious hypotension if taken with nitrates Increased production of cGMP and decreased breakdown of cGMP Page 29: Nitrates: Tachyphylaxis Tachyphylaxis of Nitrates: Tolerance occurs with frequently repeated or continuous use of high doses Attenuation of pharmacologic effects To restore responsiveness, interrupt therapy for 8-10 hours per day (nitrate-free interval) Tolerance to nitroglycerin and isosorbide, but not nitroprusside Possible mechanisms: Systemic compensation Possible inhibition of guanylate cyclase by nitrosylation Oxidation and inactivation of ALDH2, preventing enzymatic activation of nitroglycerin Page 30: Antianginal Comparison Chart Comparison of Antianginal Drugs: Nitrates: Decrease myocardial oxygen consumption (MVO2) Decrease end-diastolic volume Decrease blood pressure Increase heart rate No effect on heart contractility β-Blockers and Non-DHP CCBs: Decrease MVO2 Decrease end-diastolic volume Decrease blood pressure Decrease heart rate https://knowt.com/note/f31f5674-0271-4ee2-bab1-d0f32eecd3cb/DrugsDirectlyActingontheVasculatureV2-3 5/6 11/2/23, 2:19 PM Drugs_Directly_Acting_on_the_Vasculature.V2 (3) Decrease heart contractility Page 31: Summary Summary of Antianginal Drugs: Non-dihydropyridine CCBs cause constipation and have many drug interactions Dihydropyridine CCBs end in "pine" and cause peripheral edema and GERD Hydralazine can cause SLE (Systemic Lupus Erythematosus) Minoxidil promotes hair growth Nitroprusside can cause thiocyanate poisoning Tachyphylaxis occurs with nitroglycerin and isosorbide, but not nitroprusside Arterial CCBs: Nitroglycerin, Hydralazine, Isosorbide, Minoxidil, Nitroprusside Page 32: The End Page 33: Table I. Effect of CA-channel blockers on LES pressure in controls. Effect of CA-channel blockers on LES pressure in controls: Nifedipine (oral): Mean pressure Pre: 29.0 mmHg, Post: 9.0 mmHg Nifedipine (oral): Mean pressure Pre: 17.7 mmHg, Post: 7.7 mmHg Verapamil (i.v.): Mean pressure Pre: 20.8 mmHg, Post: 14.1 mmHg Nifedipine (sublingual): Mean pressure Pre: 13.1 mmHg, Post: 9.3 mmHg Nifedipine (oral): Mean pressure Pre: 19.1 mmHg, Post: 14.1 mmHg Diltiazem (oral): Mean pressure Pre: 18.4 mmHg, Post: 18.2 mmHg https://knowt.com/note/f31f5674-0271-4ee2-bab1-d0f32eecd3cb/DrugsDirectlyActingontheVasculatureV2-3 6/6