Cardiovascular Pharmacology – Pharmacotherapy Review
Edward JN Ishac. Ph.D.
Professor, Dept. Pharmacology & Toxicology
Office: Smith Bldg, Room 742
Email: Tel: (804) 828 2127
Table 1. Pregnancy Drug Classification (FDA, 1979)
Category: A / These drugs are the safest. Well-designed studies in people show no risks to the fetus. (eg. Folic acid, Vitamin B6)Category: B / Studies in animals show no risk to the fetus, and no well-designed studies in people have been done. OR
Studies in animals show a risk to the fetus, but well-designed studies in people do not. (eg. alpha-methyl dopa, clopidogrel, insulin, acetaminophen)
Category: C / No adequate studies in animals or people have been done. OR
In animal studies, use of the drug resulted in harm to the fetus, but no information about how the drug affects the human fetus is available.
(most drugs, 60%)
Category: D / Evidence shows a risk to the human fetus, but benefits of the drug may outweigh risks in certain situations. For example, the mother may have a life-threatening disorder or a serious disorder that cannot be treated with safer drugs (eg. Amiodarone, lithium, phenytoin, ACEIs).
Category: X / Risk to the fetus has been proved to outweigh any possible benefit
(eg. Statins, warfarin, misoprostol, thalidomide).
1. Proven safety in pregnancy (A, B):
a. Alpha-methyl dopa (B) b. Clopidogrel (B)
2. Need to weigh risk vs Benefit for use in pregnancy: (C)
a. Nifedipine (C) b. Spirolactone (C)
c. Beta-blockers (C) d. Labetalol (C)
e. Prazosin (C) f. Hydralazine (C)
g. Heparin (C) h. Ezetimibe (C)
i. Nitroglycerin (C) j. Verapamil (C)
k. Cholestyramine (C) l. Quinidine (C)
m. Hydrochlorothiazide (B) n. Sildenafil (B)
3. Not advised or Contraindicated in pregnancy (D or X):
a. ACE inhibitors (D) b. Atenolol (D)
c. ARBs (D) d. Statins (X)
e. Aliskiren (D) f. Warfarin (X)
g. Amiodarone (D) h. Phenytoin (D)
i. Aspirin (D) j. Clofibrate (C)
Figure 1. Sites of Action of Lipid-Lowering Agents
1. Resins 2. Statins (best ↓LDL) 3. Niacin (best ↑HDL)
4. Fibrates (best ↓TGs) 5. Ezetimibe 6. Omega-3 Fatty acids
Table 2. Adult Treatment Panel (ATP) III Lipid Guidelines (2004)
Desirable mg/dl / Borderline to high / High / LDL-C GoalsRF = Risk factors
Total Cholesterol / < 200 / 200-239 / > 240 / 0-1 RF, 10 yr <10% - <160 mg/dl
2 RF, 10 yr 11-20% - <130 mg/dl
CHD or CHD equivalent (ie. PAD, diabetes), 10 yr > 20% - <100 mg/dl
(optimal < 70mg/dl)
↑Risk → ↑Pharmacotherapy
LDL Cholesterol / < 130 / 130-159 / > 160
HDL Cholesterol:
Men
Women / > 40
> 50 / > 60
Triglycerides / <120-150 / 120-199 / > 200
Risk Factors: age > 45 (male) and 55 (females), family history of early vascular disease or hyperlipidemia, current smoker, elevated BP, obesity, diabetes, high LDL and low HDL.
Total-C = LDL-C + HDL-C + VLDL-C; VLDL-C = TGs/5
Table 3. Summary of Drug Classes used in Hyperlipidemia
Lipid-Lowering Agents / LDL / HDL / TGs / NotesResins (Sequestrants)
¯ Bile acid reabsorption
Cholestyramine / ¯¯ / / / Patients hate it, gritty taste, GI discomfort, constipation., LDL-Rec., VLDL, ¯ fat soluble Vits A,D,E,K, ¯warfarin, thiazide, digoxin absorption
Statins [-statins]
HMG-CoA reductase inhibitors
Atorvastatin / ¯¯¯ / / ¯ / Liver toxicity, myopathy, ¯ mylination CI: pregnancy, children. LDL-Rec, most substrates 3A4
Niacin: inhibit adipose lipolysis
(Nicotinic A. + Vit. B3)
¯ VLDL release / ¯¯ / / ¯¯ / Flushed face (¯with aspirin), GI, glucose intolerance (diabetes), gout, liver toxicity, ulcer
Fibrates: activate PPARs
Lipoprotein lipase stimulators.
Fenofibrate, Gemfibrozil / ¯ / / ¯¯¯ / Nausea, skin rash, headache, statin myopathy (fenofibrate safer). LDL synthesis, gallstone risk
Ezetimibe
Inhibit. Cholesterol absorption. / ¯¯ / / Newest class: No major adverse effects noted (↑cancer risk?), clinical benefit not proven, not frontline
Omega-3 Fatty acids
Inhibit VLDL-TG synthesis / ¯ / / ¯¯ / ↑bleeding, fishy aftertaste, diabetes, thrombocytopenia, GI disorders
Table 4. Drug Nomenclature – Suffixes, Infixes
Drug Class / Suffix / ExamplesHMG-CoA inhibitors / -vastatin / Atorvastatin, simvastatin, lovastatin
Fibrates / -fibr- / Fenofibrate, gemfibrozil, clofibrate
Beta-blockers (A-M: β1) / -olol / Propranolol, metoprolol, atenolol, [sotalol]
Alpha1-blockers / -osin / Prazosin, doxazosin, tamsulosin
ACE inhibitors / -pril / Captopril, lisinopril, enalapril
ARBs / -sartan / Losartan, valsartan, irbesartan
Renin inhibitors / -kiren / Aliskiren, remikiren
Dihydropyridines (CCBs) / -dipine / Nifedipine, amlodipine, nimodipine
PDE 5 inhibitors (cGMP) / -afil / Sildenafil, vardenafil, tadalafil
Thrombin inhibitors / -rudins / Hirudin, bivalirudin, lepirudin
LMW Heparins / -parin- / Enoxaparin, dalteparin, fondaparinux
Thrombolytic agents / -plase / Alteplase, retaplase, [streptokinase]
Drug Class
/ Hypertens. / HF / Arrhyth. / Angina /Notes / Contraindications / Cautions E. ISHAC 2010.3
Beta-Blockers (BBs) / aaaa / aaaa / aaa / aaaa / HF (CI: unstable HF, bronchospasm, bradycardia, depression); insomnia, Raynaud D. Caution in diabetes, asthma (use b1-)Ca++-Blockers (CCBs) / aaaa / aaaa / aaaa / HF, constipation, edema, rash, reflex HR (Nifed.), gingival h.
ACEI/ARB/Aliskiren / aaaa / aaaa / Angioedema, hyperkalemia, tetrogenic, glossitis, cough (acei), taste
Diuretics (Thiazides) / aaaa / aaaa / GFR >30, hypokalemia (CG); diabetes (↓glucose tol), plasma[Ca]
Glycosides: Digoxin / aa / a / Many Rx interactions, [K+] important, low K+®toxicity, ¯use HF
Vasodilators / aaa / aa / Flushing, dizziness, headache, nausea, reflex tachycardia
Na+-Channel blockers / aaaa / Effects enhanced in depolarized, damaged tissue, Phase.0, ¯CV
Nitrates / aa / aaaa / NO/cGMP, tolerance (off periods), hypotension, flushing, dizziness, headache, reflex tachycardia, many forms oral, iv, spray, patches
AGENT (Trade Name®) ANTIHYPERTENSIVE AGENTS NOTES
Diuretics I = drug interactions S = side effects CI = contraindications/cautions HT = Hypertension HF = Heart failureThiazides: Hydrochlorothiazide (Esidrix)
Metolazone, Chlorthalidone, Indapamide / Hypertension, HF, Nephrogenic DI (with low Na), act on Distal tube, plasma[Ca++] / ¯Na reabsorb, K+ loss, ¯Blood volume, CG toxicity, less effective in lean individual. Loop D. more powerful than thiazides and usually for acute use (ie edema) S: hypokalemia, ¯glucose tolerance Thz), photosensitivity, hearing loss (loop)
Loop Diuretics: Furosemide (Lasix)
Bumetanide, Torsemide, Ethacrynic acid / HF, acute hypertension, edema, act on Loop of Henle, ¯plasma[Ca++]
Potassium Sparing
Spironolactone (Aldactone) / Hypertension, Heart failure (HF)
(others Eplerenone, Triamterene) / Act on Collecting tube, no K+ loss, VG combo Rx,
block ALD (Spiro & Epler.), block Na chan (Triamt)
Acetazolamide (Diamox) / Glaucoma, reverse alkalosis, mountain s. / Proximal tube, Carbonic A inhibitor, low use
Mannitol (Osmitrol) / Acute renal failure, ¯cranial p. Rx excretion / Proximal tube, freely filtered, increase osmolarity
Angiotensin Converting Enzyme Inhibitors (ACEI) & Angiotensin Receptor Blockers (ARBs) SNS = Sympathetic nervous system
Captopril [-opril] (Capoten) / Hypertension (HT), Heart failure (HF)
ACE inhibitors (ACEI) / ¯AT-II, ¯TPR, ¯Aldosterone, ¯SNS,bradykinin
S: cough, hyperkalemia, altered taste (Zn), glossitis, food reduces absorp. CI: Low GFR, pregnancy (all)
Lisinopril (Prinivil)
Enalapril (Vasotec) / HF, Hypertension (acute & chronic) / ACEI, iv emergency HT, prodrug, T1/2 6 hr
Losartan [-sartan] (Cozaar) / HT, HF, (others Irbesartan, Valsartan) / Type AT1 blocker (ARB), as per ACEI but no cough
Aliskiren (Tekturna) / Hypertension (VG if high plasma [renin]) / direct renin inhibitor → ¯ angiotensin I, no cough
Beta-Adrenoceptor Antagonists ISA = Intrinsic sympathetic activity (partial agonist), LA = Local anesthetic action (membrane-stable)
Propranolol [ –olol] (Inderal)
(A-M b1-selective) / Hypertension, angina, arrhythmias, tremor, migraine, hyperthyroidism, panic stress / b, non-selective, LA-action, no ISA; v. useful group, depression, insomnia CI: HF, asthma, diabetes
Pindolol (Visken) / Angina, hypertension, arrhythmia / b, LA-action, ISA, angina commonly
Timolol (Blocadren) / Glaucoma, HT, angina, arrhythmia / b, no LA-action, no ISA, glaucoma (¯ secretion)
Metoprolol (Lopressor) / Hypertension, arrhythmia, HF, angina, MI / b1, LA-action, no ISA, arrhythmia, common agent
Atenolol (Tenormin) / Hypertension, angina (common), HF, MI / b1, no LA-action, no ISA, CI: pregnancy
Sotalol (Betapace) / Arrhythmia / b, no LA-action, no ISA, block K+ (class III), QT
Esmolol (Brevablock) / Arrhythmia, angina / b1, no LA-action, no ISA, very short acting (10 min)
Labetalol (Normadyne), Carvedilol (Coreg) / HT, HF (carvedilol), hypertensive crisis / b / a, some b-agonist action (Labetalol)
Calcium Channel Blockers (CCBs) DHP = Dihydropyridine class CG = Cardiac glycoside
Verapamil (Isoptin, Calan) / Hypertension, angina, arrhythmia (3A4) / Mainly cardiac, ↓HR, edema, constip. I: CG CI: HF
Diltiazem (Cardizem) / Hypertension, angina, arrhythmia / Both cardiac & arterioles, SNS, ↓HR, CI: HF
Nifedipine (Adalat) / Hypertension, Raynaud D., PAD / Mainly arterioles, HR, edema, gingival hp. CI: HF
Amlodipine (Besylate, Maleate) / Hypertension, angina, Raynaud D., PAD / Mainly arterioles, HR, edema, long acting, DHP
Drugs Acting on the Sympathetic NS italic = less important agent NE = Norepinephrine
Clonidine (Catapres) / Hypertension, opioid & nicotine withdraw
[ADHD],
(a-methyl-dopa → +Coombs test) / a2, ¯ cns sympathetic outflow, ¯ NE release, rebound HT; S: dry mouth, sedation, impotence.
a-methyl-dopa → a-methyl-NE (a2- agonist, preg)
a-Methyl-dopa (Aldomet)
Alpha-Adrenoceptor Antagonists A& C = Acute & Chronic PHT = Postural hypotension
Phenoxybenzamine (Dibenzyline) / Pheochromocytoma (a & c), HT (a & c) / a1, irreversible, S: PHT, reflex tachycardia, long act.
Phentolamine Tolazoline / Pheochromocytoma, acute HT / a, competitive, non-selective, S: PHT, reflex HR
Prazosin [-azosin] Tamsulosin / Benign prostate hypertrophy (BPH), hypertension (A & C) / a1, competitive; no reflex tachycardia, first pass effect S: PHT, nausea, drowsiness
Terazosin Doxazosin
Miscellaneous Agents [ ] = Questionable therapeutic value TCA = Tricyclic antidepressants
Dopamine (Intropin) / Shock to BP (renal vasodil.?, D,), HF / a1 / b1 / D receptors, precursor to NE, I: MAOI
Fenoldopam (Corlopam) / Acute hypertension (¯BP), renal failure / D,A -receptor agonist, SE: HR, ocular P., ¯ K+
Rarely used / Trimethapan, Mecamylamine: ¯BP, HT, Nn-ganglia blockers / Reserpine (deplete NE), Guanethidine (¯NE release); HT
Vasodilators Trade Name = (Italics)
Hydralazine (Apresoline) / Hypertension, HF (Bidil: hydralazine + isosorbide dinitrate, Afro-Amercian) / Direct vasodilate, mainly arterioles ¯TPR, combo Rx S: reflex SNS, flushing, palpitations, Lupus
Nitroprusside (Nipride) / Acute Hypertension crisis & HF / NO, cGMP, veins & arterioles ¯TPR, iv only, toxic oral S: cyanide toxicity, methhemoglobinemia
Minoxidil (Rogaine, Loniten) / Hypertension, HF, baldness / Open K+ channel, hypertrichosis, mainly arterioles, ¯TPR S: reflex SNS, fluid retention, hyperglycemia
Diazoxide (Hyperstat) / Hypertensive crisis
HEART FAILURE (HF, ‘Hormonal storm’) ( ¯CO, EDP, ejection volume <40%)
Cardiac Glycosides TI = Therapeutic index, CA = CatecholaminesDigoxin (Lanoxicaps, Lanoxin)
(¯ use for HF, caution in women) / HF, SVT (arrhythmia), Important Rx interactions: Toxicity; : Ca++ blockers ie verapamil; diuretics, quinidine, CAs, Amiod / Inhibit Na/K ATPase, [Ca++]i, [Na+]i, CO, vagus activity, low TI; kidney T1/2 35hr, S: tachycardia, visual halo, nausea, vomiting T: VT/VF; AV block
ACEI/ARBs / Lisinopril, Losartan (ARB) / Hypertension, HF / ¯ pre/afterload, use HF, break neurohumoral cycle
Positive Inotropic Agents PDE = Phosphodiesterase
Dobutamine (Dobutrex) / HF (acute), cardiac stimulant / b1, iv, CO, tolerance, may cause angina
Milrinone, Amrinone (Primacor, Inocor) / HF (chronic & acute) / Inh. PDE3, ¯pre/afterload ,cAMP, [mortality, oral]
β-Blockers / Metoprolol, Carvedilol, Bisoprolol (EBM) / Hypertension, HF (FDA approved 2002), angina, arrhythmias etc / ¯afterload, use HF, CI: for HF if bronchospasm, unstable HF, significant bradycardia (low reserve)
Vasodilators: / Hydralazine, Bidil et al / Hypertension, HF (see earlier notes) / ¯ preload, ¯ afterload, ¯ mortality, not primary Rx
Nesiritide; b-naturiuretic peptide (Natrecor) / Severe decomp HF (Class IV, acute, iv) / cGMP ® vasodilation, ¯ pre- & afterload, 20 min
Diuretics / Thiazides, Furosemide et al / Hypertension, HF (see earlier notes) / ¯ pre- & afterload, ¯congestion (furosemide) I: CG
ANGINA PECTORIS CCBs=Calcium blockers, NO=Nitric oxide
Nitroglycerin (Nitrong, Nitrogard) / Angina CI: Sildendafil (Viagra)Bioavailability (10-20%), Amyl & butyl nitrites: Volatile, recreational abuse / NO, cGMP ® vasodilation, ¯preload coronary flow, oral long duration, sublingual (fast), tolerance (drug free time) S: headache, flushing, hypotension
Isosorbide dinitrate & mononitrate
β-blockers / Propranolol etc (see earlier) / Angina, HT, arrhythmia & others / ¯ O2 demand CI: non-select. (HF), asthma, diabetes
CCBs / Verapamil, Diltiazem, Nifedipne etc / Angina, HT, arrhythmia / ¯O2 demand, dilate coronary v O2 supply; CI: HF
Peripheral Vascular Disease (PVD, PAD) DI = Drug Interactions
Aspirin / PAD, Prevent thrombosis / Inh. COX, Irrev. acetylation ¯TXA2, ¯platelet agWarfarin (Coumadin) / Pulmonary E, DVT, AF, MI Prevent thromb / Inh. Vit. K. ® ¯ II, VII, IX, X, CYP2C9, many DI
Heparin / DVT, Pulmonary E, Prevent thrombosis / Act. antithrombin III, thrombocytopenia (HIT), T 1hr
Clopidogrel (Plavix), Ticlopidine / PAD, Prevent thrombosis / Inh. ADP receptor, ¯platelet ag., cyp2C19, prodrug
Pentoxifylline (PDE4), Cilostazol (PDE3) / Intermittent claudication / Inh. PDE, cAMP, ¯platelet ag., Inh. TNFa (Pento)
Dipyridamole (Persantin) / PAD, ¯Stroke, Prevent thrombosis / Inh. TXA synthase, ¯TXA2, ¯platelet ag.,
Abciximab (Reopro) / Adjunct angioplasty, prevent thrombosis / MAB, Inh. Platelet IIB/IIA receptors, ¯platelet ag.,
Sildendafil, Vardenafil, Tadalafil / Erectile dysfunction / Inh. PDE5, cGMP, need arousal, CI: nitrates, a -B
Streptokinase, Alteplase, Reteplase / Acute MI, Pulmonary E. (clot-busters) / Activate plasminogen®dissolve clot, best < 2hr
ANTIARRHYTHMIC AGENTS SVT Supraventricular tachycardia
Phase 0:Fast upstrokeNai+ open, / Phase 1:Partial repolarization
Na+ close, K+ open/close / Phase 2:Plateau
Cai++ open, Ko+ leak / Phase 3:Repolarization
Ca++ close, Ko+ open / Phase 4:Forward current
K+ close, Na+ Ca++ leak in
Sodium Channel blockers APD = Action potential duration, CV = conduction velocity, RP = Refractory period
Quinidine Disopyrimide / Atrial arrhythmias, SVT / Class IA, Moderate block Phase 0, ¯CV, QT, APD S: M-, a-receptor (¯TPR) block, diarrhea, nausea, cardiac dep., Lupus (Proca) I: Quinidine-CG, tinnitus
Procainamide (Proneotyl) / Ventricular arrhythmias; NAPA (Class III)
Lidocaine (Xylocaine) / VT, VF (old DOC), iv, im / Class IB, Minimal block Phase 0, shorten Phase 3, ¯CV (least), phenytoin-gingival H. T: least toxicity