CARDIO PHARM Flashcards
Short-Acting Dihydropyridines Calcium channel blockers (CCBs) Agents
Nifedipine Clevidipine Nimodipine Half-life < 2 hours Not indicated for monotherapy of angina because they cause hypotension and secondary reflex tachycardia, which can worsen cardiac ischemia.
Intermediate-Acting Dihydropyridines Calcium channel blockers (CCBs) Agents
Nitrendipine Nicardipine Lercanidipine Half-life 8-12 hours
Long-Acting Dihydropyridines Calcium channel blockers (CCBs) Agents
Amlodipine Felodipine Half-life > 24 hours
Nondihydropyridines Agents
Benzothiazepines → diltiazem Phenylalkylamines → verapamil, gallopamil
Calcium channel blockers (CCBs) Clinical Use
All CCBs 1. Arterial hypertension (esp. amlodipine) (amlodipine is the CCB most commonly used in hypertension because it causes vasodilation without having negative inotropic/dromotropic effects on the heart) 2. Stable angina→ for patients with contraindications for beta blockers or who are not responsive to beta blockers (negative effects on contractility, heart rate, and rhythm decrease myocardial oxygen demand and improve angina symptoms) 3. Vasospastic angina (Prinzmetal angina) (CCBs dilate the coronary arteries and decrease/reverse coronary artery spasm) 4. Achalasia (reserved for patients who cannot undergo surgical/endoscopic intervention) 5. Diffuse esophageal spasm Dihydropyridines 1. Raynaud phenomenon (e.g., nifedipine, felodipine) 2. Subarachnoid hemorrhage → nimodipine (to prevent secondary vasospasm) 3. Tocolysis 4. Gestational hypertension 5. Hypertensive urgency/hypertensive emergency → nicardipine, clevidipine 6. Thromboangiitis obliterans Nondihydropyridines 1. Supraventricular arrhythmias (verapamil and diltiazem) (these are both categorized as class IV antiarrhythmic drugs) - Supraventricular tachycardia - Atrial fibrillation, atrial flutter (to control the heart rate of stable patients with atrial fibrillation) 2. Cardiomyopathy (hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy) 3. Migraine 4. Verapamil → cluster headache prophylaxis
Dihydropyridines Calcium channel blockers (CCBs) Adverse Effects
Effects due to vasodilation 1. Peripheral edema (esp. amlodipine) (vasodilation of resistance vessels increases the hydrostatic pressure within the capillaries, causing an efflux of plasma into the interstitial space) 2. Headaches, dizziness 3. Facial flushing, feeling of warmth 4. Reflex tachycardia → a condition of tachycardia secondary to a decrease in blood pressure (esp. nifedipine) - Vasodilation lowers the blood pressure, which stimulates baroreceptors of the sympathetic nervous system, resulting in reflex tachycardia. - May worsen symptoms of angina (reflex tachycardia increases myocardial oxygen demand, which can result in angina) Gingival hyperplasia
Nondihydropyridines Calcium channel blockers (CCBs) Adverse Effects
- Have been shown to increase lithium concentration - Can cause theophylline toxicity due to inhibition of hepatic cytochrome oxidases (narrow therapeutic index) Diltiazem → similar to those of the other CCB classes, but milder (the exception is reflex tachycardia, a side effect seen only with short-acting and intermediate-acting dihydropyridines (e.g., nifedipine, clevidipine, nimodipine)) Verapamil and Gallopamil - Reduced contractility - Bradycardia - AV block (due to suppression of the SA node and decreased AV node conduction velocity) - Gingival hyperplasia Verapamil - Constipation - Hyperprolactinemia (CCBs reduce the production of dopamine in the CNS, causing an increase in serum prolactin) - Can cause digoxin toxicity due to decrease clearance (because verapamil binds to albumin as this drug)
Calcium channel blockers (CCBs) Contraindications
All CCBs 1. Allergy/hypersensitivity to CCBs 2. Symptomatic hypotension (the vasodilation and myocardial depression caused by CCBs will further decrease cardiac output and blood pressure) 3. Acute coronary syndrome (several recent studies suggest that CCBs increase the mortality rate of patients with acute coronary syndrome) Dihydropyridines 1. Hypertrophic obstructive cardiomyopathy (HOCM) (dihydropyridines worsen HOCM symptoms and can cause syncope and sudden death in affected individuals) 2. Severe stenotic heart valve defects (the potent vasodilatory effects of dihydropyridines cause coronary hypoperfusion and systemic hypotension, which can result in myocardial ischemia in individuals with severe stenotic heart valve defects) Nondihydropyridines - Preexisting cardiac conduction disorders (the myocardial depressant effect of nondihydropyridines (i.e., their negative inotropic and dromotropic effect on the heart) decreases cardiac contractility and conduction velocity, which can worsen preexisting cardiac dysfunction in affected individuals) 1. Wolff-Parkinson-White syndrome (CCBs depress AV node conduction, causing the current to pass through the accessory pathway (bundle of Kent), which results in ventricular tachycardia) 2. Sick sinus syndrome 3. Systolic dysfunction (in congestive heart failure) 4. Bradycardia 5. 2° AV block/3° AV block - Combination with beta blockers → risk of AV block, bradycardia, and/or decreased cardiac contractility
Hydralazine
Mechanism: Increase cGMP –> smooth muscle relaxation. Vasodilates arterioles > veins Afterload reduction. Metabolized via phase II acetylation in the liver Clinical Use: Severe hypertension (particularly acute), HF (with organic nitrate). Safe to use during pregnancy. Frequently coadministered with a β-blocker to prevent reflex tachycardia. Adverse Effects: Compensatory tachycardia (contraindicated in angina/CAD), sodium and water retention, peripheral edema, headache, angina. SLE-like syndrome.
Nitroprusside
Mechanism: Short acting vasodilator (arteries = veins) (vs. nitrates veins < arteries) Metabolized in the body to release nitric oxide and cyanide ions Increase cGMP via direct release of NO. Decrease preload –> decrease EDV and pulmonary capillary wedge pressure Activated non-enzymatically; therefore the onset of action is immediate Clinical Use: Use to treat hypertensive emergency Adverse Effect: Can cause cyanide toxicity (releases cyanide).
Hypertensive Emergency Treatment
Treat with clevidipine, fenoldopam, labetalol, nicardipine, or nitroprusside.
Fenoldopam
Mechanism: Dopamine D1 receptor agonist—coronary, peripheral, renal, and splanchnic vasodilation. Decrease BP Renal vasodilation is particularly prominent and leads to increased renal perfusion, diuresis, and natriuresis. This makes fenoldopam especially beneficial in patients with acute kidney injury. Clinical Use: Use to treat hypertensive emergency Also used postoperatively as an antihypertensive. Adverse Effects: Can cause hypotension and tachycardia. Hemodynamic Changes: Decrease BP (vasodilation), increase HR, increase CO
Nitrates Clinical Use
- Angina pectoris - Short-acting nitrates such as sublingual nitroglycerin, isosorbide dinitrate, or nitroglycerin spray for treatment of acute attacks - Long-acting nitrates such as isosorbide mononitrate can be taken regularly (2–3 times daily) for anginal prophylaxis → unlike some other nitrates, isosorbide mononitrate does not undergo first-pass metabolism by the liver and thus has ∼100% bioavailability. 2. Hypertensive crisis → short-term reduction of blood pressure 3. Acute coronary syndrome 4. Hypertensive pulmonary edema 5. Chronic heart failure (used with hydralazine as second-line treatment in cases in which ACE inhibitor, beta-blocker, diuretic, digoxin, or aldosterone antagonist therapy fail; improves both symptoms and survival, but has less survival benefit than ACE inhibitors)
Nitrates Mechanism
- Organic nitrates (nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate) require activation by mitochondrial aldehyde reductase, therefore, the onset of action is not immediate. - Sodium nitroprusside is activated non-enzymatically; therefore the onset of action is immediate - Oral nitrates undergo extensive first-pass metabolism in the liver. Exogenous supply of nitric oxide (NO) through nitrate → activation of guanylyl cyclase → ↑ cyclic guanosine monophosphate (cGMP) → activation of protein kinase G - Increases SERCA activity → ↓ intracellular calcium → ↓ recruitment of contractile units → vasodilation - Increases myosin light chain phosphatase activity → ↓ phosphorylated myosin → smooth muscle relaxation → vasodilation 1. Peripheral vasodilation - Decreased preload through venous dilation (venous pooling) → reduces myocardial wall tension → improved myocardial perfusion - Decreased afterload → reduces contraction effort → ↓ myocardial oxygen demand (this effect is caused by dilation of the arteries and can only be achieved at higher doses.) - Greater vasodilatory effect on veins than arteries (except for sodium nitroprusside) (due to rapid-onset non-enzymatic release of NO, it exhibits both venous and arterial effects) 2. Coronary dilation → improved myocardial perfusion (nitrates are also used in the treatment of coronary artery spasm (via muscle relaxation) in vasospastic (Prinzmetal) angina) - In patients with atherosclerotic CAD, arterioles are already dilated to maximize cardiac blood flow (due to flow-limiting stenosis) → difficult to dilate coronary vessels further → limited effect of nitrates Anginal pain relief → ↓ preload through venous pooling → ↓ heart size → ↓ oxygen demand → ↓ pain
Nitrates Adverse Effects
- Circulatory dysregulation - Hypotension, reflex sympathetic activity → reflex tachycardia → nitrate syncope - Beta blockers can be applied to counter this mechanism 2. Nitrate-induced headache (due to the dilation of the cerebral arteries) 3. Flushing 4. Gastroesophageal reflux (due to the relaxation of the lower esophageal sphincter) 5. Development of tolerance (over time, the effectiveness of nitrates declines. The prognosis is also not improved by long-term therapy, and may even deteriorate instead) - Prevention → intermittent therapy with nitrate-free intervals of at least 8 hours 6. Cyanide toxicity after sodium nitroprusside infusion 7. Methemoglobinemia 8. “Monday disease” → industrial workers who are exposed to nitrates during the work week develop a tolerance over the course of the week. No exposure during weekends leads to loss of tolerance. Reexposure on Monday causes dizziness, tachycardia, and headache.
Nitrates Contraindications
- Hypotension - Risk of life-threatening hypotension if taken within 24 hours of a PDE-5 inhibitor (e.g., patients with angina pectoris) 2. Stenosis of the left ventricular ejection tract (e.g., aortic stenosis, hypertrophic cardiomyopathy) 3. Myocardial infarction with right ventricular failure 4. Increased intracranial pressure
Nitroglycerin
Organic nitrate require activation by mitochondrial aldehyde reductase, therefore, the onset of action is not immediate. Mechanism: Exogenous supply of nitric oxide (NO) through nitrate → activation of guanylyl cyclase → ↑ cyclic guanosine monophosphate (cGMP) → activation of protein kinase G - Increases SERCA activity → ↓ intracellular calcium → ↓ recruitment of contractile units → vasodilation - Increases myosin light chain phosphatase activity → ↓ phosphorylated myosin → smooth muscle relaxation → vasodilation 1. Peripheral vasodilation - Decreased preload through venous dilation (venous pooling) → reduces myocardial wall tension → improved myocardial perfusion - Greater vasodilatory effect on veins than arteries (except for sodium nitroprusside) (due to rapid-onset non-enzymatic release of NO, it exhibits both venous and arterial effects) 2. Coronary dilation → improved myocardial perfusion (nitrates are also used in the treatment of coronary artery spasm (via muscle relaxation) in vasospastic (Prinzmetal) angina) Clinical Use: 1. Angina pectoris - Short-acting nitrate for treatment of acute attacks 2. Acute coronary syndrome 3. Hypertensive pulmonary edema 4. Chronic heart failure (used with hydralazine as second-line treatment in cases in which ACE inhibitor, beta-blocker, diuretic, digoxin, or aldosterone antagonist therapy fail; improves both symptoms and survival, but has less survival benefit than ACE inhibitors) Adverse Effects: 1. Circulatory dysregulation - Hypotension, reflex sympathetic activity → reflex tachycardia → nitrate syncope - Beta blockers can be applied to counter this mechanism 2. Nitrate-induced headache (due to the dilation of the cerebral arteries) 3. Flushing 4. Gastroesophageal reflux (due to the relaxation of the lower esophageal sphincter) 5. Development of tolerance (over time, the effectiveness of nitrates declines. The prognosis is also not improved by long-term therapy, and may even deteriorate instead) - Prevention → intermittent therapy with nitrate-free intervals of at least 8 hours 6. “Monday disease” → industrial workers who are exposed to nitrates during the work week develop a tolerance over the course of the week. No exposure during weekends leads to loss of tolerance. Reexposure on Monday causes dizziness, tachycardia, and headache. Contraindications: 1. Hypotension - Risk of life-threatening hypotension if taken within 24 hours of a PDE-5 inhibitor (e.g., patients with angina pectoris) 2. Stenosis of the left ventricular ejection tract (e.g., aortic stenosis, hypertrophic cardiomyopathy) 3. Myocardial infarction with right ventricular failure 4. Increased intracranial pressure
Ranolazine
Mechanism: - Metabolic modulator that reduces myocardial oxygen demand without altering the heart rate, blood pressure, contractility, and/or end-diastolic volume - Inhibition of late inward sodium channels on cardiac myocytes → reduced calcium influx (via sodium-calcium channel pump) → reduced wall stress and oxygen demand - Decreased rate of fatty acid beta-oxidation (aerobic process) with a simultaneous increase in glycolysis (anaerobic process) Clinical Use: Stable angina refractory to other medical therapies. Adverse Effects: Constipation, dizziness, headache, nausea
Sacubitril
Mechanism: Neprilysin inhibitor Prevents degradation of natriuretic peptides, angiotensin II, and substance P by neprilysin Increase vasodilation Decrease ECF volume. Clinical Use: Used in combination with an ARB (valsartan) for treatment of HFrEF. Adverse Effects: Hypotension, hyperkalemia, cough, dizziness Contraindicated with ACE inhibitors due to angioedema (both drugs increase bradykinin)
Statins Mechanism
Competitive inhibition of HMG-CoA reductase renders this enzyme unable to convert HMG-CoA to mevalonate (the rate-limiting step of cholesterol synthesis) → reduced intrahepatic cholesterol biosynthesis → upregulation of expression of LDL receptor gene via sterol regulatory element-binding protein (SREBP) → increased LDL recycling and: - ↓↓ LDL cholesterol - ↑ HDL cholesterol - ↓ Triglyceride level Pleiotropic effect: - ↓ C-reactive protein - ↑ Plaque stabilization - ↑ Anti-inflammatory effect - Antioxidant effect and improved endothelial function of coronary arteries
Statins Clinical Use
- Patients with a clinical atherosclerotic cardiovascular disease (includes coronary artery disease, stroke, and peripheral arterial disease) - Patients with LDL cholesterol elevated ≥ 190 mg/dL (first-line treatment) - Patients with diabetes and multiple risk factors - Primary prevention of atherosclerotic cardiovascular disease (ASCVD) - First-line therapy for hypercholesterolemia. Significantly reduces the risk of mortality in patients suffering from CAD. Ideally administered in the evenings (especially simvastatin) (endogenous synthesis of cholesterol peaks in the evening. This is less relevant for atorvastatin due to long half life) Combination therapy with bile acid resins has a stronger hypolipidemic effect compared to treatment with statins alone (both groups of drugs increase LDL receptor expression)
Statins Adverse Effects
General (common) → headache and gastrointestinal symptoms (e.g., constipation, diarrhea, flatulence) Hepatic → (up to 3% of patients) ↑ LFTs due to the involvement of cytochrome P450 systems (CYP3A4 and CYP2C9) in the breakdown of statins (statins involved include simvastatin, atorvastatin, lovastatin, fluvastatin. Change medication or lower the dose if LFTs > 3 times the normal value. Obtain baseline LFT prior to treatment) Muscular → statins decrease the synthesis of coenzyme Q10 and impair energy production within the muscle. - Myalgia (muscle pain) → continue treatment as long as creatinine phosphokinase (CK) remain normal Statin-associated myopathy - Muscle pain and weakness, especially when used alongside fibrates or niacin - Myositis → ↑ CK (muscle-specific CK levels may be up to 10 times normal levels. Obtain baseline CK levels prior to treatment) - May progress to rhabdomyolysis (rare but severe side-effect that may lead to myoglobulinuria → AKI (↑ BUN and ↑ creatinine)) - Management → discontinue statin therapy for 2–4 weeks; start treatment with a low-dose statin (e.g., pravastatin or fluvastatin) once symptoms have resolved (these statins have been shown to have the lowest risk of muscular side effects. If symptoms of myopathy do not occur, the dose can be adjusted to achieve the goals outlined in the guidelines for lipid-lowering therapy) - Treatment must be discontinued if myopathy/rhabdomyolysis occurs.
Statins Contraindications
- Hypersensitivity 2. Active liver disease 3. Muscle disorder 4. Pregnancy, breastfeeding (cholesterol-lowering agents inhibit the development of the placenta and the fetus because cholesterol is essential for growth and development)
Statins Interaction
Additive myocyte toxicity - Fibrates - Corticosteroids - Colchicine (also competes with statins for CYP3A4 metabolism) - Nicotinic acid CYP3A4 inhibitors (statins metabolized by CYP3A4 (simvastatin, lovastatin, and atorvastatin) must not be combined with CYP3A4 inhibitors, since doing so increases statin concentrations and, thus, the risk of rhabdomyolysis!) - HIV/HCV protease inhibitors - Macrolides (especially erythromycin and clarithromycin) - Azole antifungals - Cyclosporine (also inhibits organic ion transport protein (OITP)) - Nondihydropyridine CCBs (eg, verapamil, diltiazem) Warfarin (warfarin is primarily metabolized by CYP2C9. Fluvastatin, pitavastatin, and rosuvastatin potentiate the effects of warfarin effects by competitively inhibiting CYP2C9, increasing the INR and the risk of bleeding)
Bile Acid Resins (Cholestyramine, Colestipol, Colesevelam) Mechanism
Ion exchange resin binds bile acids in the intestine (the active ingredient is bound to chloride anions. Bile acids displace the chloride anions in the intestine forming cholestyramine-bile acid complexes) → interruption of enterohepatic circulation (↓ bile acid absorption and ↑ bile acid excretion) (cholestyramine intake results in the removal of bile acids from the body, as bile acids are usually primarily reabsorbed in the ileum) → lowers cholesterol pool and promotes synthesis of LDL receptors (↓↓ unbound LDL), slightly ↑ HDL, and slightly ↑ triglycerides (increased bile acid synthesis activates liver enzymes that concurrently increase production of triglycerides)
Bile Acid Resins (Cholestyramine, Colestipol, Colesevelam) Clinical Use
- Combination treatment with statins in hypercholesterolemia 2. Digitoxin overdose 3. Pruritus associated with elevated bile acid levels (cholestasis) 4. Bile acid diarrhea
Bile Acid Resins (Cholestyramine, Colestipol, Colesevelam) Adverse Effects
- Gastrointestinal → nausea, abdominal bloating and cramping (colesevelam is the least likely bile acid resin to induce adverse GI effects) 2. ↑ LFTs 3. Myalgia
Bile Acid Resins (Cholestyramine, Colestipol, Colesevelam) Contraindications
- Hypertriglyceridemia > 300–500 mg/dL 2. Hypertriglyceridemia-induced pancreatitis 3. Bowel obstruction
Bile Acid Resins (Cholestyramine, Colestipol, Colesevelam) Drug Interactions
Reduces absorption of warfarin, digoxin, and fat-soluble vitamins (this interaction can be minimized by administering bile acid resins four hours before or one hour after administering these drugs)
Cholestyramine
Bile Acid Resin Mechanism of action - Ion exchange resin binds bile acids in the intestine (the active ingredient is bound to chloride anions. Bile acids displace the chloride anions in the intestine forming cholestyramine-bile acid complexes) → interruption of enterohepatic circulation (↓ bile acid absorption and ↑ bile acid excretion) (cholestyramine intake results in the removal of bile acids from the body, as bile acids are usually primarily reabsorbed in the ileum) → lowers cholesterol pool and promotes synthesis of LDL receptors (↓↓ unbound LDL), slightly ↑ HDL, and slightly ↑ triglycerides (increased bile acid synthesis activates liver enzymes that concurrently increase production of triglycerides) Clinical Use: 1. Combination treatment with statins in hypercholesterolemia 2. Digitoxin overdose 3. Pruritus associated with elevated bile acid levels (cholestasis) 4. Bile acid diarrhea Adverse effects 1. Gastrointestinal → nausea, abdominal bloating and cramping (colesevelam is the least likely bile acid resin to induce adverse GI effects) 2. ↑ LFTs 3. Myalgia Contraindications 1. Hypertriglyceridemia > 300–500 mg/dL 2. Hypertriglyceridemia-induced pancreatitis 3. Bowel obstruction Drug interactions → reduces absorption of warfarin, digoxin, and fat-soluble vitamins (this interaction can be minimized by administering bile acid resins four hours before or one hour after administering these drugs)
Colestipol
Bile Acid Resin Mechanism of action - Ion exchange resin binds bile acids in the intestine (the active ingredient is bound to chloride anions. Bile acids displace the chloride anions in the intestine forming cholestyramine-bile acid complexes) → interruption of enterohepatic circulation (↓ bile acid absorption and ↑ bile acid excretion) (cholestyramine intake results in the removal of bile acids from the body, as bile acids are usually primarily reabsorbed in the ileum) → lowers cholesterol pool and promotes synthesis of LDL receptors (↓↓ unbound LDL), slightly ↑ HDL, and slightly ↑ triglycerides (increased bile acid synthesis activates liver enzymes that concurrently increase production of triglycerides) Clinical Use: 1. Combination treatment with statins in hypercholesterolemia 2. Digitoxin overdose 3. Pruritus associated with elevated bile acid levels (cholestasis) 4. Bile acid diarrhea Adverse effects 1. Gastrointestinal → nausea, abdominal bloating and cramping (colesevelam is the least likely bile acid resin to induce adverse GI effects) 2. ↑ LFTs 3. Myalgia Contraindications 1. Hypertriglyceridemia > 300–500 mg/dL 2. Hypertriglyceridemia-induced pancreatitis 3. Bowel obstruction Drug interactions → reduces absorption of warfarin, digoxin, and fat-soluble vitamins (this interaction can be minimized by administering bile acid resins four hours before or one hour after administering these drugs)
Colesevelam
Bile Acid Resin Mechanism of action - Ion exchange resin binds bile acids in the intestine (the active ingredient is bound to chloride anions. Bile acids displace the chloride anions in the intestine forming cholestyramine-bile acid complexes) → interruption of enterohepatic circulation (↓ bile acid absorption and ↑ bile acid excretion) (cholestyramine intake results in the removal of bile acids from the body, as bile acids are usually primarily reabsorbed in the ileum) → lowers cholesterol pool and promotes synthesis of LDL receptors (↓↓ unbound LDL), slightly ↑ HDL, and slightly ↑ triglycerides (increased bile acid synthesis activates liver enzymes that concurrently increase production of triglycerides) Clinical Use: 1. Combination treatment with statins in hypercholesterolemia 2. Digitoxin overdose 3. Pruritus associated with elevated bile acid levels (cholestasis) 4. Bile acid diarrhea Adverse effects 1. Gastrointestinal → nausea, abdominal bloating and cramping (colesevelam is the least likely bile acid resin to induce adverse GI effects) 2. ↑ LFTs 3. Myalgia Contraindications 1. Hypertriglyceridemia > 300–500 mg/dL 2. Hypertriglyceridemia-induced pancreatitis 3. Bowel obstruction Drug interactions → reduces absorption of warfarin, digoxin, and fat-soluble vitamins (this interaction can be minimized by administering bile acid resins four hours before or one hour after administering these drugs)
Ezetimibe Mechanism
Mechanism of action: - Selective inhibition of cholesterol reabsorption at the brush border of enterocytes (cholesterol transporter NPC1L1) → ↓↓ LDL, little effect on HDL (slight ↑) and triglycerides (slight ↓) (ezetimibe leads to a marked reduction in LDL cholesterol. However, recent studies show that vessel wall thickness remains unaffected by treatment. Therefore, there may not be a positive change in the risk of vascular occlusion)
Ezetimibe Clinical Use
- Monotherapy → in contraindications or statin intolerance 2. Combination therapy (statin and ezetimibe) → in insufficient LDL cholesterol reduction by statins (various studies show an additional reduction of up to 25% with combination therapy)
Ezetimibe Adverse Effects
Rare, except in combination therapy - ↑ Liver enzymes - Angioedema - Diarrhea - Myalgia
Ezetimibe Contraindication
Coadministration with a statin during active liver disease
Fibrates (fibric acid derivatives) (bezafibrate, fenofibrate, and gemfibrozil) Mechanism
Activation of the peroxisome proliferator-activated receptor alpha (PPAR–α) → ↑ lipoprotein lipase activity → more rapid degradation of LDL and triglycerides and induction of HDL synthesis → ↓ LDL, ↑ HDL, ↓↓↓ triglyceride
Bezafibrate
Mechanism of action: - Activation of the peroxisome proliferator-activated receptor alpha (PPAR–α) → ↑ lipoprotein lipase activity → more rapid degradation of LDL and triglycerides and induction of HDL synthesis → ↓ LDL, ↑ HDL, ↓↓↓ triglyceride Clinical Use: - Second-line drug of choice in hyperlipidemia, most effective for lowering triglycerides Adverse effects - Dyspepsia - Myopathy, especially in combination with statins (may be mediated by the competitive inhibition of CYP3A4 → reduction in statin metabolism) - Cholelithiasis (fibrates inhibit cholesterol 7α hydroxylase → decreased bile acid synthesis → supersaturation of bile with cholesterol (↑ cholesterol:bile acid ratio)) - ↑ LFTs - Mild decrease in hemoglobin, hematocrit, and WBC upon initiation; normally stabilizes with long-term therapy Contraindications 1. Renal insufficiency (fibrates are contraindicated in renal insufficiency because they are excreted by the kidneys. There is a risk of drug accumulation, which can further increase the risk of side effects) 2. Liver failure 3. Gall bladder diseases Interactions → enhance the effect of other drugs (e.g., sulfonylureas, warfarin) by inhibiting hepatic CYP450 (the reason for the enhanced effect is the strong binding of fibrates to albumin. The dose of warfarin should be reduced by 30% when using fibrates)
Fenofibrate
Mechanism of action: - Activation of the peroxisome proliferator-activated receptor alpha (PPAR–α) → ↑ lipoprotein lipase activity → more rapid degradation of LDL and triglycerides and induction of HDL synthesis → ↓ LDL, ↑ HDL, ↓↓↓ triglyceride Clinical Use: - Second-line drug of choice in hyperlipidemia, most effective for lowering triglycerides Adverse effects - Dyspepsia - Myopathy, especially in combination with statins (may be mediated by the competitive inhibition of CYP3A4 → reduction in statin metabolism) - Cholelithiasis (fibrates inhibit cholesterol 7α hydroxylase → decreased bile acid synthesis → supersaturation of bile with cholesterol (↑ cholesterol:bile acid ratio)) - ↑ LFTs - Mild decrease in hemoglobin, hematocrit, and WBC upon initiation; normally stabilizes with long-term therapy Contraindications 1. Renal insufficiency (fibrates are contraindicated in renal insufficiency because they are excreted by the kidneys. There is a risk of drug accumulation, which can further increase the risk of side effects) 2. Liver failure 3. Gall bladder diseases Interactions → enhance the effect of other drugs (e.g., sulfonylureas, warfarin) by inhibiting hepatic CYP450 (the reason for the enhanced effect is the strong binding of fibrates to albumin. The dose of warfarin should be reduced by 30% when using fibrates)
Gemfibrozil
Mechanism of action: - Activation of the peroxisome proliferator-activated receptor alpha (PPAR–α) → ↑ lipoprotein lipase activity → more rapid degradation of LDL and triglycerides and induction of HDL synthesis → ↓ LDL, ↑ HDL, ↓↓↓ triglyceride Clinical Use: - Second-line drug of choice in hyperlipidemia, most effective for lowering triglycerides Adverse effects - Dyspepsia - Myopathy, especially in combination with statins (may be mediated by the competitive inhibition of CYP3A4 → reduction in statin metabolism) - Cholelithiasis (fibrates inhibit cholesterol 7α hydroxylase → decreased bile acid synthesis → supersaturation of bile with cholesterol (↑ cholesterol:bile acid ratio)) - ↑ LFTs - Mild decrease in hemoglobin, hematocrit, and WBC upon initiation; normally stabilizes with long-term therapy Contraindications 1. Renal insufficiency (fibrates are contraindicated in renal insufficiency because they are excreted by the kidneys. There is a risk of drug accumulation, which can further increase the risk of side effects) 2. Liver failure 3. Gall bladder diseases Interactions → enhance the effect of other drugs (e.g., sulfonylureas, warfarin) by inhibiting hepatic CYP450 (the reason for the enhanced effect is the strong binding of fibrates to albumin. The dose of warfarin should be reduced by 30% when using fibrates)
Fibrates (fibric acid derivatives) (bezafibrate, fenofibrate, and gemfibrozil) Clinical Use
Second-line drug of choice in hyperlipidemia, most effective for lowering triglycerides
Fibrates (fibric acid derivatives) (bezafibrate, fenofibrate, and gemfibrozil) Adverse Effects
- Dyspepsia - Myopathy, especially in combination with statins (may be mediated by the competitive inhibition of CYP3A4 → reduction in statin metabolism) - Cholelithiasis (fibrates inhibit cholesterol 7α hydroxylase → decreased bile acid synthesis → supersaturation of bile with cholesterol (↑ cholesterol:bile acid ratio)) - ↑ LFTs - Mild decrease in hemoglobin, hematocrit, and WBC upon initiation; normally stabilizes with long-term therapy
Fibrates (fibric acid derivatives) (bezafibrate, fenofibrate, and gemfibrozil) Contraindications
- Renal insufficiency (because they are excreted by the kidneys. There is a risk of drug accumulation, which can further increase the risk of side effects) 2. Liver failure 3. Gall bladder diseases
Fibrates (fibric acid derivatives) (bezafibrate, fenofibrate, and gemfibrozil) Interactions
Enhance the effect of other drugs (e.g., sulfonylureas, warfarin) by inhibiting hepatic CYP450 (the reason for the enhanced effect is the strong binding of fibrates to albumin. The dose of warfarin should be reduced by 30% when using fibrates)
Niacin Mechanism
Inhibits lipolysis and fatty acid release in adipose tissue through blockade of hormone-sensitive lipase and ↓ hepatic VLDL synthesis → ↓ triglyceride, ↓↓ LDL synthesis, ↑↑ HDL
Cardiac Glycosides (Digitalis, Digoxin, Ouabain) Mechanism
- Onset of effect - Oral → 0.5–2 h - IV → 15–30 min - Half-life → 36 - 40 hours - Protein binding → 20–40% (digoxin binds to proteins in the blood and other tissues to a significant extent. Therefore, it has a large volume of distribution) - Elimination → renal (substance accumulates in the case of renal failure) Inhibition of Na+/K+-ATPase → higher intracellular Na+ concentration → reduced efficacy of Na+/Ca2+ exchangers → higher intracellular Ca2+ concentration - In cardiomyocytes, this leads to increased contractility (positive inotropic effect), reduced velocity of electric conduction (negative dromotropic effect) via AV node depression, and a reduction of the heart rate (negative chronotropic effect) via SA node depression. - In neurons of the vagal nerve, this leads to reduced velocity of electric conduction, which causes reduced heart rate (via a reflexive reduction of sympathetic transmission). Cardiac glycosides inhibit Na+/K+-ATPase, increasing cardiac contractility and decreasing AV conduction and heart rate!
Cardiac Glycosides (digitalis, digoxin, ouabain) Clinical Use
- Congestive heart failure (symptomatic patients with NYHA ≥ II despite pharmacotherapy)
- Atrial fibrillation
- Supraventricular tachycardia
Cardiac Glycosides (digitalis, digoxin, ouabain) Adverse Effects
- Cholinergic—nausea, vomiting, diarrhea, blurry yellow vision (think van Gogh), arrhythmias, AV block.
- Can lead to hyperkalemia, which indicates poor prognosis.
Cardiac Glycosides (digitalis, digoxin, ouabain) Interactions
K+-depleting diuretics → hypokalemia → arrhythmias Verapamil, diltiazem, amiodarone, quinidine → possible overdose (reduce digoxin dose to avoid overdose)
Digitalis
Cardiac Glycoside Onset of effect - Oral → 0.5–2 h - IV → 15–30 min Half-life → 36 - 40 hours Protein binding → 20–40% (digoxin binds to proteins in the blood and other tissues to a significant extent. Therefore, it has a large volume of distribution) Elimination → renal (substance accumulates in the case of renal failure) Mechanism: Inhibition of Na+/K+-ATPase → higher intracellular Na+ concentration → reduced efficacy of Na+/Ca2+ exchangers → higher intracellular Ca2+ concentration - In cardiomyocytes, this leads to increased contractility (positive inotropic effect), reduced velocity of electric conduction (negative dromotropic effect) via AV node depression, and a reduction of the heart rate (negative chronotropic effect) via SA node depression. - In neurons of the vagal nerve, this leads to reduced velocity of electric conduction, which causes reduced heart rate (via a reflexive reduction of sympathetic transmission). Cardiac glycosides inhibit Na+/K+-ATPase, increasing cardiac contractility and decreasing AV conduction and heart rate! Clinical Use: 1. Congestive heart failure (symptomatic patients with NYHA ≥ II despite pharmacotherapy) 2. Atrial fibrillation 3. Supraventricular tachycardia Adverse Effects: - Cholinergic—nausea, vomiting, diarrhea, blurry yellow vision (think van Gogh), arrhythmias, AV block. - Can lead to hyperkalemia, which indicates poor prognosis. Contraindications: - Ventricular fibrillation - Use with caution in pregnant women and in patients with: 1. Electrolyte and fluid disorders (e.g., volume depletion, hypokalemia, hypomagnesemia, and/or hypercalcemia (these conditions increase the effect of cardiac glycosides)) 2. Cardiovascular disorders (e.g., acute coronary syndrome, AV blocks, Wolff-Parkinson-White syndrome, hypertrophic obstructive cardiomyopathy, sick sinus syndrome) 3. Renal failure (can lead to digoxin overdose and, vice versa, digoxin can also cause/worsen renal failure) 4. Certain medications (K+-depleting diuretics, verapamil, diltiazem, amiodarone, quinidine) Intereactions: 1. K+-depleting diuretics → hypokalemia → arrhythmias 2. Verapamil, diltiazem, amiodarone, quinidine → possible overdose (reduce digoxin dose to avoid overdose)
Digoxin
Cardiac Glycoside Onset of effect - Oral → 0.5–2 h - IV → 15–30 min Half-life → 36 - 40 hours Protein binding → 20–40% (digoxin binds to proteins in the blood and other tissues to a significant extent. Therefore, it has a large volume of distribution) Elimination → renal (substance accumulates in the case of renal failure) Mechanism: Inhibition of Na+/K+-ATPase → higher intracellular Na+ concentration → reduced efficacy of Na+/Ca2+ exchangers → higher intracellular Ca2+ concentration - In cardiomyocytes, this leads to increased contractility (positive inotropic effect), reduced velocity of electric conduction (negative dromotropic effect) via AV node depression, and a reduction of the heart rate (negative chronotropic effect) via SA node depression. - In neurons of the vagal nerve, this leads to reduced velocity of electric conduction, which causes reduced heart rate (via a reflexive reduction of sympathetic transmission). Cardiac glycosides inhibit Na+/K+-ATPase, increasing cardiac contractility and decreasing AV conduction and heart rate! Clinical Use: 1. Congestive heart failure (symptomatic patients with NYHA ≥ II despite pharmacotherapy) 2. Atrial fibrillation 3. Supraventricular tachycardia Adverse Effects: - Cholinergic—nausea, vomiting, diarrhea, blurry yellow vision (think van Gogh), arrhythmias, AV block. - Can lead to hyperkalemia, which indicates poor prognosis. Contraindications: - Ventricular fibrillation - Use with caution in pregnant women and in patients with: 1. Electrolyte and fluid disorders (e.g., volume depletion, hypokalemia, hypomagnesemia, and/or hypercalcemia (these conditions increase the effect of cardiac glycosides)) 2. Cardiovascular disorders (e.g., acute coronary syndrome, AV blocks, Wolff-Parkinson-White syndrome, hypertrophic obstructive cardiomyopathy, sick sinus syndrome) 3. Renal failure (can lead to digoxin overdose and, vice versa, digoxin can also cause/worsen renal failure) 4. Certain medications (K+-depleting diuretics, verapamil, diltiazem, amiodarone, quinidine) Intereactions: 1. K+-depleting diuretics → hypokalemia → arrhythmias 2. Verapamil, diltiazem, amiodarone, quinidine → possible overdose (reduce digoxin dose to avoid overdose)
Ouabain
Cardiac Glycoside Onset of effect - Oral → 0.5–2 h - IV → 15–30 min Half-life → 36 - 40 hours Protein binding → 20–40% (digoxin binds to proteins in the blood and other tissues to a significant extent. Therefore, it has a large volume of distribution) Elimination → renal (substance accumulates in the case of renal failure) Mechanism: Inhibition of Na+/K+-ATPase → higher intracellular Na+ concentration → reduced efficacy of Na+/Ca2+ exchangers → higher intracellular Ca2+ concentration - In cardiomyocytes, this leads to increased contractility (positive inotropic effect), reduced velocity of electric conduction (negative dromotropic effect) via AV node depression, and a reduction of the heart rate (negative chronotropic effect) via SA node depression. - In neurons of the vagal nerve, this leads to reduced velocity of electric conduction, which causes reduced heart rate (via a reflexive reduction of sympathetic transmission). Cardiac glycosides inhibit Na+/K+-ATPase, increasing cardiac contractility and decreasing AV conduction and heart rate! Clinical Use: 1. Congestive heart failure (symptomatic patients with NYHA ≥ II despite pharmacotherapy) 2. Atrial fibrillation 3. Supraventricular tachycardia Adverse Effects: - Cholinergic—nausea, vomiting, diarrhea, blurry yellow vision (think van Gogh), arrhythmias, AV block. - Can lead to hyperkalemia, which indicates poor prognosis. Contraindications: - Ventricular fibrillation - Use with caution in pregnant women and in patients with: 1. Electrolyte and fluid disorders (e.g., volume depletion, hypokalemia, hypomagnesemia, and/or hypercalcemia (these conditions increase the effect of cardiac glycosides)) 2. Cardiovascular disorders (e.g., acute coronary syndrome, AV blocks, Wolff-Parkinson-White syndrome, hypertrophic obstructive cardiomyopathy, sick sinus syndrome) 3. Renal failure (can lead to digoxin overdose and, vice versa, digoxin can also cause/worsen renal failure) 4. Certain medications (K+-depleting diuretics, verapamil, diltiazem, amiodarone, quinidine) Intereactions: 1. K+-depleting diuretics → hypokalemia → arrhythmias 2. Verapamil, diltiazem, amiodarone, quinidine → possible overdose (reduce digoxin dose to avoid overdose)
Cardiac Glycosides (Digitalis, Digoxin, Ouabain) Poisoning Etiology
- Digoxin overdose (iatrogenic, by nonadherence to prescribed dosages or by ingestion of plants containing cardiac glycosides) (plants of the genus Digitalis, also known as foxglove, are natural sources of digoxin. Other cardiac glycosides are found in lilies of the valley, oleander, and pheasant’s eye (Adonis vernalis)) 2. Ouabain poisoning (Ouabain is a cardiac glycoside derived from plants such as Strophanthus gratus. It works by inhibiting the potassium-binding site on the Na+/K+-ATPase. It is rarely, if ever, used clinically) 3. Hypokalemia, because digitalis compounds compete with K+ for binding of Na+/K+-ATPase (the less K+ there is to compete for binding sites, the more digitalis can bind; therefore, symptoms of digitalis poisoning become more severe when extracellular K+ concentration decreases) 4. Renal failure → ↓ digoxin excretion 5. Treatment with verapamil, diltiazem, amiodarone, and/or quinidine → removal of digoxin from binding site in body tissues and ↓ renal elimination (both factors lead to increased digoxin serum levels) 6. Volume depletion (e.g., treatment with diuretics)
Cardiac Glycosides (Digitalis, Digoxin, Ouabain) Poisoning Presentation
- Via cholinergic agonism → nausea, vomiting, diarrhea, abdominal pain, and anorexia 2. Visual disturbances - Xanthopsia (yellow-tinted vision) - Photophobia - Blurry vision with a yellow tint and halos 3. Disorientation, weakness 4. Palpitations (due to arrhythmias or AV block)
Cardiac Glycosides (Digitalis, Digoxin, Ouabain) Poisoning Findings
ECG → potentially severe cardiac arrhythmias - Premature ventricular beats - T-wave inversion or flattening - Deformed ST segment (“scooped” or “sagging” ST segments) - ↓ QT interval - ↑ PR interval - Atrial tachycardia with AV block Laboratory studies - Serum digoxin concentration (ideally, measure 6 hours after ingestion) - Serum electrolyte levels → hyperkalemia (associated with poor prognosis) resulting from inhibition of the Na+/K+-ATPase (inhibition of Na+/K+-ATPase leads to decreased K+ influx into heart and skeletal muscle cells, causing serum K+ levels to increase. In acute cardiac glycoside poisoning, the degree of hyperkalemia correlates with the mortality rate) - Creatinine and blood urea nitrogen to evaluate renal function
Cardiac Glycosides (Digitalis, Digoxin, Ouabain) Poisoning Treatment
- Digoxin-specific antibody (œ) fragments (anti-digoxin Fab fragments)
- Atropine for symptomatic bradycardia
- Slowly normalize serum potassium levels
- Magnesium
- Class IB antiarrhythmics
- Temporary cardiac pacing
