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USMLE (Fach) / Pharmacology - Cardiovascular (Lektion)

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• Hydralazine ↑ cGMP → smooth muscle relaxation. Vasodilates arterioles > veins; afterload reduction. Clinical use:- Severe hypertension (particularly acute)- HF (with NO)- Safe to use during pregnancy.- Frequently coadministered with a β-blocker to prevent reflex tachycardia. Adverse effects: Compensatory tachycardia (contraindicated in angina/CAD), fluid retention, headache, angina. SLE-like syndrome.
• HMG-CoA reductase inhibitors Lovastatin, pravastatin LDL ↓↓↓ HDL ↑Triglycerids ↓ Inhibit conversion of HMG-CoA to mevalonate, a cholesterol precursor; ↓ mortality in CAD patients. Side effects: - Hepatotoxicity (↑ LFTs)- Myopathy (esp. when used with fibrates or niacin)
• Bile acid resins Cholestyramine, colestipol, colesevelam LDL ↓↓HDL slightly ↑Triglycerides slightly ↑ Prevent intestinal reabsorption of bile acids; liver must use cholesterol to make more. Side effects: GI upset, ↓ absorption of other drugs and fat-soluble vitamins
• Ezetimibe Prevents cholesterol absorption at the small intestine brush border by inhibiting the Niemann-Pick C1-like 1 (NPC1L1) transporter protein, which transports dietary cholesterol from the gastrointestinal lumen into intestinal enterocytes. LDL ↓↓HDL ↑/–Triglycerides ↓/– Side effect: Rare ↑ LFTs, diarrhea
• Fibrates Gemfibrozil, bezafibrate, fenofibrate LDL ↓ HDL ↑Triglycerids ↓↓↓ Upregulate LPL → ↑ TG clearance, decrease VLDL productionActivates PPAR-α to induce HDL synthesis Side effect: - Myopathy (↑ risk with statins)- Cholesterol gallstones (via inhibition of cholesterol 7α-hydroxylase)
• Niacin (vitamin B3) - Inhibits lipolysis (hormone sensitive lipase) in adipose tissue- Reduces hepatic VLDL synthesis LDL ↓↓HDL ↑↑Triglycerides ↓ Adverse effects:- Red, flushed face, which is ↓ by NSAIDs or long-term use- Hyperglycemia- Hyperuricemia
• Digoxin Direct inhibition of Na+/K+ ATPase → indirect inhibition of Na+/Ca2+ exchanger.↑ [Ca2+]i → positive inotropy. Stimulates vagus nerve → ↓ HR. Clinical use:- Heart failure (↑ contractility)- Atrial fibrillation (↓ conduction at AV node and depression of SA node) Adverse effects:- Nausea, vomiting, diarrhea, anorexia, blurry yellow vision, arrhythmias, AV block.- Can lead to hyperkalemia, which indicates poor prognosis.- Factors predisposing to toxicity: renal failure (↓ excretion), hypokalemia (permissive for digoxin binding at K+-binding site on Na+/K+ ATPase), drugs that displace digoxin from tissue-binding sites, and ↓ clearance (eg, verapamil, amiodarone, quinidine). Antidote: Slowly normalize K+, cardiac pacer, anti-digoxin Fab fragments, Mg2+.
• Antiarrhythmics - Class Ia Quinidine, Procainamide, Disopyramide (The Queen proclaims Diso's pyramid) - ↑ AP duration, ↑ effective refractory period (ERP), ↑ QT interval, some potassium channel blocking effects. Clinical use: Atrial and ventricular arrhythmias, especially re-entrant and ectopic SVT and VT. Adverse effects:- Cinchonism (headache, tinnitus with quinidine)- Reversible SLE-like syndrome (procainamide)- HF (disopyramide)- Thrombocytopenia- Torsades de pointes due to ↑ QT interval
• Antiarrhythmics - Class Ib Lidocaine, Mexiletine (I'd buy Liddy's Mexican Tacos) - ↓ AP duration- Preferentially affect ischemic or depolarized Purkinje and ventricular tissue. - Phenytoin can also fall into the Ib category. Clincial use:- Acute ventricular arrhythmias (especially post-MI)- Digitalis-induced arrhythmias Adverse effects: CNS stimulation/depression, cardiovascular depression
• Antiarrhythmics - Class Ic Flecainide, Propafenone (Can I have fries, please?) - Significantly prolongs ERP in AV node and accessory bypass tracts.- No effect on ERP in Purkinje and ventricular tissue.- Minimal effect on AP duration. (Ia ↑, Ib ↓, Ic –) Clinical use:- SVTs, including atrial fibrillation.- Only as a last resort in refractory VT. Adverse effects:- Proarrhythmic, especially post-MI (Ic is contraindicated in structural and ischemic heart disease)
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• Antiarrhythmics - Class II (β-blockers) Metoprolol, propanolol, esmolol, atenolol, timolol, carvedilol - Decrease SA and AV nodal activity by ↓ cAMP, ↓ Ca2+ currents. Suppress abnormal pacemakers by ↓ slope of phase 4.- AV node particularly sensitive – ↑ PR interval. - Esmolol very short acting. Clinical use:- SVT- Ventricular rate control for atrial fibrillation and atrial flutter. Adverse effects:- Impotence- Exacerbation of COPD and asthma- Bradycardia, AV block, HF- CNS effects (sedation, sleep alterations)- May mask signs of hypoglycemia- Metoprolol can cause dyslipidemia.- Propanolol can exacerbate vasospasm in Prinzmetal angina.- β-blockers (except the nonselective α- and β-antagonists carvedilol and labetalol) cause unapposed α1-agonist if given alone for pheochromocytome or cocaine toxicity. - Treat β-blocker overdose with saline, atropine, glucagon.
• Antiarrhythmics - Class III (potassium channel blockers) Amiodarone, Ibutilide, Dofetilide, Sotalol (AIDS) - ↑ AP duration, ↑ ERP, ↑ QT interval Clinical use:- Atrial fibrillation, atrial flutter- Ventricular tachycardia (amiodarone, sotalol) Adverse effects:- Sotalol – torsades de pointes, excessive β blockade- Ibutilide – torsades de pointes- Amiodarone – pulmonary fibrosis, hepatotoxicity, hypo-/hyperthyroidism (40% iodine!), acts as hapten (corneal deposits, blue/gray skin deposits resulting in photodermatitis), neurologic effects, constipation, cardiovascular effects (bradycardia, heart block, HF). Check PFTs, LFTs, and TFTs. Lipophilic. Has class I, II, III, and IV effects.
• Antiarrhythmics - Class IV (calcium channel blockers) Verapamil, diltiazem - ↓ conduction velocity, ↑ ERP, ↑ PR interval Use: Prevention of nodal arrhythmias (eg, SVT), rate control in atrial fibrillation. Adverse effects:- Constipation, flushing, edema, cardiovascular effects (HF, AV block, sinus node depression)
• Magnesium - Antiarrhythmic Use:- Torsades de pointes (may be caused by class Ia and class III antiarrhythmias) - Effective in digoxin toxicity
• AT-receptor blockers Losartan - block AT1 receptors - Same results as ACE-inhibitors on BP mechanisms
• Renin inhibitor Aliskiren - blocks formation of angiotensin I - same results as ACE-inhibitors on BP mechanisms
• Nitroprusside - ↓ TPR via dilation of both arterioles and venules Use: hypertensive emergencies (used IV) Side effect:- cyanide toxicity
• Minoxidil - Opens K+ channel, causing hyperpolarziation of smooth muscle - Results in arteriolar vasodilation Use:- Severe hypertension- slows hair loss Side effects:- hypertrichosis- Reflex tachycardia
• Treatment of pulmonary hypertension Bosentan- Endothelin-IA-receptor antagonist- Side effects associated with vasodilation (headache, flushing, hypotension, etc)- Contraindication: pregnancy Sidenafil- Inhibits type V PDE- ↑ cGMP- Pulmonary artery relaxation- ↓ pulmonary hypertension Prostacyclin (PGI2): Epoprostenol
• Calcium channel blockers Amlodipine, clevidipine, nicardipine, nifedipine, nimodipine (dihydropyridines, act on vascular smooth muscle).Diltiazem, verapamil (non-dihydropyridines, act on heart). Block voltage-dependent L-type Ca2+ channels in of cardiac and smooth muscle → ↓ muscle contractility.- Results in ↓ intracellular Ca2+- Causes ↓ CO (verapamil and diltiazem), ↓ TPR (all CCBs) Use:- Dihydropyridines (except nimodipine): hypertension, angina (including Prinzmetal), Raynaud phenomenon.- Nimodipine: subarachnoid hemorrhage (prevents cerebral vasospasm).- Nicardipine, clevidipine: hypertensive urgency or emergency.Non-dihydropyridines: hypertension, angina, atrial fibrillation/flutter. Adverse effects:- Dihydropyridine: peripheral edema, flushing, dizziness- Non-dihydropyridine: cardiac depression, AV block, hyperprolactinemia, constipation, gingival hyperplasia
• Wolff-Parkinson-White Syndrome therapy - arrhythmetics Ia or III (block accessory pathway) - Avoid digoxin, β-blocker, Ca2+ channel blockers, adenosin (slow AV conduction)
• Nesiritide - recombinant form of B-type natriuretic peptide (BNP) - binds to natriuretic peptide receptors, thus ↑ cGMP, resulting in vasodilation - Used in acutely decompensated CHF
• Adenosine Antiarrhymic Causes Gi-coupled decrease in cAMP.- ↑ K+ out of cells → hyperpolarizing the cell and ↓ ICa, decreasing AV node conduction.- ↓ SA and AV nodal activity- Affects phase 4 of the action potential, reducing the rate of spontaneous depolarization. Drug of choice in diagnosing/terminating certain forms of supraventricular tachycardias (SVTs). - Administered IV, extremely short duration (~15 sec)- Effects blunted by theophylline and caffeine (adenosine receptor antagonists) Adverse effects: flushing, hypotension, chest pain, sense of impending doom, bronchospasm.
• Nitrates Nitroglycerin, isosorbide dinitrate, isosorbide mononitrate.- Nitroglycerin: sublingual, transdermal, IV- Isosorbide: oral, extended release for chronic use Vasodilate by ↑ NO in vascular smooth muscle → ↑ cGMP and smooth muscle relaxation. - Dilate veins >> arteries. - ↓ preload Clinical use: Angina, acute coronary syndrome, pulmonary edema. Adverse effects:- Flushing, headache, orthostatic hypotension- "Monday disease" in industrial exposure: tolerance for the vasodilating action during the work week and loss of tolerance over the weekend → tachycardia, dizziness, headache- Reflex tachycardia (treat with β-blockers) - Contraindicated in right ventricular infarction.
• Ranolazine Inhibits the late phase of sodium current thereby reducing diastolic wall tension and oxygen consumption. Does not affect heart rate or contractility. Use: Angina refractory to other medical therapies. Adverse effects: Constipation, dizziness, headache, nausea, QT prologation.
• Orlistat - Therapeutic use: weight loss - inhibits pancreatic lipase --> ↓ triglyceride breakdown in the intestine Side effects:- oily stools (steatorrhea)- diarrhea- ↓ absorption of lipid-soluble vitamins
• Hypertension treatment Primary (essential) hypertension: Thiazide diuretics, ACE inhibitors, angiotensin II receptor blockers (ARBs), dihydropyridine Ca2+ channel blockers. Hypertension with heart failure: Diuretics, ACE inhibitors/ARBs, β-blockers, aldosterone antagonists.- β-blockers are contraindicated in cardiogenic shock.- In HF, ARBs may be combined with the neprilysin inhibitor sacubitril. Hypertension with diabetes mellitus: ACE inhibitors/ARBs, Ca2+ channel blockers, thiazide diuretics, β-blockers- ACE inhibitors/ARBs are protective against diabetic nephropathy. Hypertension in pregnancy: Hydralazine, labetalol, methyldopa, nifedipine Hypertension in asthma: ARBs, Ca2+ channel blocks, thiazide diuretics, selective β-blockers.- Avoid nonselective β-blockers to prevent β2-receptor-induced bronchoconstriction. Avoid ACE inhibitors to prevent confusion between drug or asthma-related cough.
• Hypertensive emergency Treat with clevidipine, fenoldopam, labetalol, nicardipine, or nitroprusside. Nitroprusside: Short acting; ↑ cGMP via direct release of NO. Can cause cyanide toxicity (releases cyanide). Fenoldopam: Dopamine D1 receptor agonist – coronary, peripheral, renal, and splanchnic vasodilation. ↓ BP, ↑ natriuresis. Also used postoperatively as an antihypertensive. Can cause hypotension and tachycardia.
• Milrinone Selective PDE-3 inhibitor.  In cardiomyocytes: ↑ cAMP accumulation → ↑ Ca2+ influx → ↑ inotropy and chronotropy.In vascular smooth muscle: ↑ cAMP accumulation → inhibition of MLCK activity → general vasodilation. Use: Short-term use in acute decompensated HF. Adverse effects: Arrhythmias, hypotension.
• PCSK9 inhibitors Alirocumab, evolocumab LDL ↓↓↓HDL ↑Triglycerids ↓ Inactivation of LDL-receptor degradation, increasing amount of LDL removed from bloodstream Side effects: Myalgias, delirium, dementia, other neurocognitive effects
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• Ivabradine Selective inhibition of funny sodium channels (If), prolonging slow depolarization phase 4.↓ SA node firing; negative chronotropic effect without inotropy. Reduces cardiac O2 requirement. Clinical use: - Chronic stable angina in patients who cannot take β-blockers. - Chronic HF with reduced ejection fraction. Side effect: Luminous phenomena/visual brightness, hypertension, bradycardia.
• Neprylisin Metalloprotease that cleaves and inactivates endogenous peptides including natriuretic peptides (eg, BNP), glucagon, oxytocin and bradykinin. Inhibition of neprilysin leads to increased levels of endogenous natriuretic peptides, which promote beneficial effects (diuresis, natriuresis, vasodilatory effect) in heart failure.
• Cilostazol Phosphodiesterase 3 inhibitor with therapeutic focus on cAMP. It inhibits platelet aggregation and widens arteries (direct arterial vasodilator). Use: Intermittent claudication in patients with peripheral vascular disease.

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