CV Pharmacology

Drugs for primary (essential) HTN
Diuretics, ACE Inhibitors, ARBs, Calcium Channel Blockers

Drugs for HTN associated with CHF
Diuretics, ACE Inhibitors/ARBs, Beta Blockers (compensated CHF only; contraindicated in cardiogenic shock and used cautiously in decompensated CHF), Aldosterone Antagonists

Drugs for HTN associated with DM
ACE inhibitors/ARBs (protective against diabetic nephropathy), Calcium Channel Blockers, Diuretics, Beta Blockers, Alpha Blockers

Calcium Channel Blocker; (dihydropyridine)

Calcium Channel Blocker; (dihydropyridine)

Calcium Channel Blocker; (dihydropyridine)

Calcium Channel Blocker; (non-dihydropyridine)

Calcium Channel Blocker; (non-dihydropyridine)

Calcium Channel Blockers: Mechanism of Action
Block voltage dependent L-type Calcium channels in cardiac and smooth muscle, thereby reducing muscle contractility (and .: reducing myocardial oxygen demand).

In the vascular smooth muscle: amlodipine & nifedipine>diltiazem>verapamil

In the heart: verapamil>diltiazem>amlodipine & nifedipine (verapamil = ventricle)

Calcium Channel Blockers: Clinical Use
Dihydropyridines (except nimodipine): HTN, angina, Raynaud phenomenon

Non-dihydropyridines: HTN, angina, atrial fibrillation/flutter

Nimodipine: subarachnoid hemorrhage (prevents cerebral vasospasm)

Calcium Channel Blockers: Toxicity
Cardiac depression, AV block, (negative ionotropy), peripheral edema, flushing, dizziness, hyperprolactinemia, constipation

Hydralazine: Mechanism of Action
Increase cGMP –> smooth muscle relaxation.

Vasodilates arterioles>veins, Reduces afterload

(NO also increases cGMP, but it works more on veins than arterioles)

Hydralazine: Clinical Use
Severe HTN, CHF

First line treatment for HTN in pregnancy, with methyldopa.

Frequently co-administered with a beta-blocker to prevent reflex tachycardia.

Hydralazine: Toxicity
Compensatory tachycardia (contraindicated in angina/CAD), fluid retention, nausea, headache, angina. Lupus-like syndrome.

Drugs used in hypertensive emergency
nitroprusside, nicardipine, clevidipine, labetalol, fenoldopam

Short acting

Increases cGMP via direct NO release

Can cause cyanide toxicity (releases cyanide). CN toxicity manifests as confusion/disorientation, lactic acidosis. Antidote: sodium thiosulfate (sulfer binds CN).

Dopamine D1 receptor agonist. Induces coronary, peripheral, renal, splanchnic vasodilation.

Decreases BP and increases natriuresis

Nitroglycerin and isosorbide dinitrate: Mechanism of Action
Vasodilates by increasing NO in vascular smooth muscle –> increased cGMP and smooth muscle relaxation

Dilates veins >> arteries, reduces preload

Nitroglycerin and isosorbide dinitrate: Clinical Use
Angina, acute coronary syndrome, pulmonary edema

Nitroglycerin and isosorbide dinitrate: Toxicity
Reflex tachycardia (treat with B-blockers), hypotension, flushing, headache, “Monday disease” in industrial exposure (development of tolerance for vasodilating action during the work week and loss of tolerance over the weekend resulting in tachycardia, dizziness, headache upon reexposure)

Goal of antianginal therapy
Reduce myocardial O2 consumption (MVO2) by decreasing: end-diastolic volume, blood pressure, heart rate, and/or contractility

Effect of nitrates in treating angina
Affect preload

Decrease end-diastolic volume
Decrease BP
Increase contractility (reflex response)
Increase HR (reflex response)
Decrease ejection time
Decrease MVO2

Note: nifedipine (Calcium channel blocker) has similar effect to nitrates

Effect of B-blockers in treating angina
Affect afterload

Increase end-diastolic volume
Decrease BP
Decrease contractility
Decrease HR
Increase ejection time
Decrease MVO2

Note: verapamil (Calcium channel blocker) has similar effect to B-blockers

Note: pindolol and acebutolol are partial B-agonists and are contraindicated in angina

Effect of nitrates + B-blockers in treating angina
No effect or decrease end-diastolic volume
Decrease BP
Little/no effect on contractility
No effect or Decrease HR
Little/no effect on ejection time
DECREASE MVO2 (more than either individually)

HMG-CoA Reductase inhibitors: Examples of drugs, and effect on LDL, HDL, Triglycerides
Statins: lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin

Decrease LDL (more than other lipid lowering agents)
Increase HDL
Decrease Triglycerides

HMG-CoA Reductase inhibitors: Mechanism of Action and Toxicity
Mechanism: Inhibit conversion of HMG-CoA to mevalonate (a cholesterol precursor)

Toxicity: Hepatotoxicity (increases LFTs), rhabdomyolysis (especially when used with fibrates and niacin)

Niacin (Vitamin B3): Effect on LDL, HDL, Triglycerides
Decrease LDL
Increase HDL (more than other lipid lowering agents)
Decrease Triglycerides

Niacin (Vitamin B3): Mechanism of Action and Toxicity
Mechanism: Inhibits lipolysis in adipose tissue; reduces hepatic VLDL synthesis

Toxicity: Red, flushed face that is reduced with aspirin use or long time niacin use; Hyperglycemia (acanthosis nigricans); Hyperuricemia (exacerbates gout)

Bile acid resins: Examples of drugs, and effect on LDL, HDL, Triglycerides
Cholestyramine, colestipol, colesevelam

Decrease LDL
Slight increase HDL
Slight increase Triglycerides

Bile acid resins: Mechanism of Action and Toxicity
Mechanism: Prevent intestinal reabsorption of bile acids; liver must use cholesterol to make more

Toxicity: tastes bad, GI discomfort, decreased absorption of fat-soluble vitamins, cholesterol gall stones

Cholesterol absorption blockers: Examples of drugs, and effect on LDL, HDL, Triglycerides

Decreases LDL
No effect on HDL
No effect on Triglycerides

Cholesterol absorption blockers: Mechanism of Action and toxicity
Mechanism: Prevent cholesterol reabsorption at small intestine brush border

Toxicity: Rare increase in LFTs, diarrhea

Fibrates: Examples of drugs, and effect on LDL, HDL, Triglycerides
Gemfibrozil, clofibrate, bezafibrate, fenofibrate

Decreases LDL
Increases HDL
Decreases Triglycerides (more than other lipid lowering agents)

Fibrates: Mechanism of Action and Toxicity
Mechanism: Upregulate Lipoprotein lipase –> increased triglyceride clearance; activated PPAR-alpha to induce HDL synthesis

Toxicity: Myositis (risk increased with concurrent statin use), hepatotoxicity (increased LFTs), cholesterol gallstones (especially with concurrent bile acid resins)

Lipid-Lowering Agents (diagram)
Lipid-Lowering Agents (diagram)

Cardiac Glycosides: Examples of drugs, Mechanism of Action, Clinical Use
Digoxin (75% bioavailability, 20-40% protein bound, t1/2= 40hours, urinary excretion)

Mechanism: Direct inhibition of Na/K ATPase, which leds to indirect inhibition of Na/Ca exhanger/antiporter. Intracellular Calcium increases –> positive ionotropy. Stimulates vagus nerve, which decreases HR.

Decreasing HR while increasing contractility leads to increased SV and the heart overall working more efficiently.

Clinical Use: CHF (to increase contractility), AFib (to decrease conduction at AV node and depress SA node)

Digoxin toxicity
-Cholinergic: nausea, vomiting, diarrhea, blurry yellow vision
-ECG: increased PR, decreased QT, ST scooping, T-wave inversion, arrhythmia, AV block
-Can cause hyperkalemia (indicates poor prognosis)
-Predisposing factors for toxicity: Renal failure (b/c of decreased excretion), hypokalemia (allows for binding at K binding site of Na/K ATPase), verapamil, amiodarone, quinidine (decrease digoxin clearance, displace digoxin from tissue biding sites)

Antidote: slowly normalize K, cardiac pacer, anti-digoxin Fab fragments, Mg++

Na+ Channel Blockers: Class IA

Examples of drugs, Mechanism of Action, Clinical Use, Toxicity
Na+ Channel Blockers: Class IA

Examples of drugs, Mechanism of Action, Clinical Use, Toxicity

Quinidine, Procainamide, Disopyramide

Mechanism: Increase AP duration, Increase effective refractory period, Increase QT Interval

Clinical Use: Atrial and Ventricular arrhythmias, especially re-entrant and ectopic SVT and VT

Toxicity: Cinchonism (headache, tinnitus with quinidine), reversible SLE-like syndrome (procainamide), heart failure (disopyramide), thrombocytopenia, torsades de pointes due to increased QT interval

Na+ Channel Blockers: Class IB

Examples of drugs, Mechanism of Action, Clinical Use, Toxicity
Na+ Channel Blockers: Class IB

Examples of drugs, Mechanism of Action, Clinical Use, Toxicity

Lidocaine, Mexiletine, Phenytoin

Mechanism: Decreased AP duration. Preferentially affect ischemic or depolarized Purkinje and ventricle tissue.

Clinical Use: Acute ventricular arrhythmias (especially post-MI), digitalis-induced arrhythmias. (IB Is Best post-MI)

Toxicity: CNS stimulation/depression, Cardiovascular depression

Na+ Channel Blockers: Class IC

Examples of drugs, Mechanism of Action, Clinical Use, Toxicity
Na+ Channel Blockers: Class IC

Examples of drugs, Mechanism of Action, Clinical Use, Toxicity

Flecainide, Propafenone

Mechanism: Significantly prolongs refractory period in AV node, minimal effect on AP duration

Clinical Use: SVTs, including AFib. Only used as last resort in refractory VT.

Toxicity: Proarrhythmic, especially post-MI (contraindicated). (IC Is Contraindicated in structural and ischemic heart disease.)

Beta Blockers: Class II

Examples of drugs, Mechanism of Action, Clinical Use, Toxicity

Metropolol, propranolol, esmolol, atenolol, timolol, carvedilol

Mechanism: Decrease SA and AV nodal activity by decreasing cAMP. Decreased Ca currents. Suppress abnormal pacemakers by decreaseing slope of phase 4.

Note: Av node is particularly sensitive-> increased PR interval.
Note: Esmolol is very short acting.

Clinical Use: SVT, slowing ventricular rate during AFib and AFlutter

Toxicity: Impotence, exacerbation of COPD and asthma, CV effects (bradycardia, AV block, CHF), CNS Effects (sedation, sleep alteration). May mask the signs of hypoglycemia.

Metropolol can cause dyslipidemia. Propranolol can exacerbate vasospasm in Prinzmetal angina.

Contraindicated in cocaine users (risk of unopposed alpha-adrenergic receptor agonist activity).

Treat overdose with glucagon.

K+ Channel Blockers: Class III

Examples of drugs, Mechanism of Action, Clinical Use, Toxicity

Amiodorone, Ibutilide, Dofetilide, Sotalol (mnemonic: AIDS)

Mechanism: Increased AP duration, Increased effective refractory period. Used when other antiarrhythmics fail. Increases QT interval.

Clinical Use: AFib, AFlutter, Ventricular tachycardia (amiodorone, sotalol)

Sotalol- torsades de pointes, excessive B blockade
Ibutilide- torsades de pointes
Amiodarone- pulmonary fibrosis, hepatotoxicity, hypothyroidism/hyperthyroidism (amiodarone is 40% Iodine by weight), corneal deposits, skin deposits (blue/gray) resulting in photodermatitis, neurological effects, constipation, cardiovascular effects (bradycardia, heart block, CHF)

Note: Remember to check PFTs, LFTs, TFTs when using amiodarone. Amiodarone has class I, II, III, IV effects and alters the lipid membrane

Ca Channel Blockers: Class IV

Examples of drugs, Mechanism of Action, Clinical Use, Toxicity

Verapamil, diltiazem

Mechanism: Decreased conduction velocity, Increased effective refractory period, Increased PR interval

Clinical Use: Prevention of nodal arrhythmias (eg, SVT), rate control of AFib

Toxicity: Constipation, flushing, edema, CV effects (CHF, AV block, sinus node depression)

Increases K out of cells -> hyperpolarizing the cell and decreased Intracellular Ca.

Drug of choice in diagnosing/abolishing supraventricular tachycardia.

Very short acting (~15sec)

Adverse Effects: flushing, hypotension, chest pain

Effects are blocked by theophylline and caffeine

Effective in torsades de pointes and digoxin toxicity

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