Download Drug Summary Review: HT, CG, Ang, Arr

Cardiovascular Pharmacology – Pharmacotherapy Review
Edward JN Ishac. Ph.D.
Professor, Dept. Pharmacology & Toxicology
Office: Smith Bldg, Room 742
Email: [email protected] Tel: (804) 828 2127
3
1
4
2
5
1. Resins
4. Fibrates (best ↓TGs)
2. Statins (best ↓LDL)
5. Ezetimibe
3. Niacin (best ↑HDL)
Desirable
mg/dl
Borderline
to high
High
Notes
Total Cholesterol
< 200
200-239
> 240
LDL Cholesterol
< 130
130-159
> 160
High >160mg/dl with CAD or
more than 2 risk factors
Optimal <100mg/dl
HDL Cholesterol:
Men
Women
Triglycerides
> 40
> 50
<120-150
> 60
120-199
> 200
10 Year CHD Risk
>20% High risk (aggressive)
10-19% Moderate
<10% Low risk
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.
↑Risk → ↑Pharmacotherapy.
LDL-C = Total-C – HDL-C – VLDL-C; VLDL-C = TGs/5
Drug Class
Hypertens.
HF
Beta-Blockers
 
Arrhyth.
Angina
Notes / Contraindications / Cautions
E. ISHAC 2010.1






Many Rx interactions, [K+] important, low K+toxicity, use HF

Flushing, dizziness, headache, nausea, reflex tachycardia

Effects enhanced in depolarized, damaged tissue, Phase.0, CV

 NO/cGMP, tolerance (off periods), hypotension, flushing, dizziness,
HF (CI: unstable HF, bronchospasm, bradycardia, depression);
insomnia, Raynaud D. Caution in diabetes, asthma (use 1-)
Ca++-Blockers (CCBs) 
  HF, constipation, edema, rash, reflex HR (Nifed.), gingival h.
ACEI / ARB
Angioedema, hyperkalemia, tetrogenic, glossitis, cough (acei), taste
  

Diuretics (Thiazides)   
GFR >30, hypokalemia (CG); diabetes (↓glucose tolerance)



Na+-Channel blockers
Nitrates





Cardiac glycosides
Vasodilators
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 failure
Thiazides: Hydrochlorothiazide (Esidrix) Hypertension, HF, Nephrogenic DI (with
Na reabsorb, K+ loss, Blood volume, CG
Metolazone
(Zaroxolyn, Mykrox) low Na), act on Distal tube, plasma[Ca++] toxicity, less effective in lean individual. Loop
diuretics more powerful than thiazides and usually
Loop Diuretics
HF, acute hypertension, edema, act on
for acute use (ie edema) S: hypokalemia, glucose
Furosemide
(Lasix) Loop of Henle, plasma[Ca++]
tolerance Thz), photosensitivity, hearing loss (loop)
Potassium Sparing
Hypertension, Heart failure (HF)
Act on Collecting tube, no K+ loss, very good combo
Spironolactone
(Aldactone) (others Eplerenone, Triamterene)
Rx, block aldosterone action (Spironolactone, Epler.)
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]
AT-II, TPR, Aldosterone, SNSbradykinin
S: cough, hyperkalemia, altered taste (Zn), glossitis,
food reduces absorp. CI: Low GFR, pregnancy
ACEI, iv emergency HT, poor oral absorpt., T1/2 6 hr
(Capoten) Hypertension, Heart failure (HF)
(Prinivil) ACE inhibitors (ACEI)
Lisinopril
Enalapril
(Vasotec) HF, Hypertension (acute & chronic)
Losartan
[-sartan]
(Cozaar) HT, HF, (others Irbesartan, Valsartan)
Aliskiren
AT1 blocker (ARB), as per ACEI but no dry cough
direct renin inhibitor →  production of angiotensin I
(Tekturna) Hypertension
Beta-Adrenoceptor Antagonists
ISA = Intrinsic sympathetic activity (partial agonist), LA = Local anesthetic action (membrane-stable)
(Inderal) Hypertension, angina, arrhythmias, tremor,  non-selective, LA-action, no ISA; v. useful group,
migraine, hyperthyroidism, panic stress
depression, insomnia CI: HF, asthma, diabetes
(Visken) Angina, hypertension, arrhythmia
 LA-action, ISA, angina commonly
Propranolol
[ –olol]
(A-M 1-selective)
Pindolol
Timolol
(Blocadren)
Metoprolol
, no LA-action, no ISA, glaucoma common
Glaucoma, decrease secretion; (HT)
1, LA-action, no ISA, arrhythmia, common agent
(Lopressor) Hypertension, arrhythmia, HF, angina
Atenolol
(Tenormin) Hypertension, angina, HF
1, no LA-action, no ISA, angina, common agent
Sotalol
(Betapace) Arrhythmia
, no LA-action, no ISA, block K+ (class III), QT
Esmolol
(Brevablock)
1, no LA-action, no ISA, very short acting (10 min)
Arrhythmia, angina
 / , some -agonist action (Labetalol)
DHP = Dihydropyridine class
CG = Cardiac glycoside
Labetalol (Normadyne), Carvedilol (Coreg) Hypertension, HF, hypertensive crisis
Calcium Channel Blockers (CCBs)
Verapamil
(Isoptin, Calan) Hypertension, angina, arrhythmia
Diltiazem
(Cardizem)
Nifedipine
(Adalat)
Amlodipine
(3A4) Mainly cardiac, edema, constipation I: CG CI: HF
Hypertension, angina, arrhythmia
Both cardiac & arterioles,  SNS, HR, CI: HF 
Hypertension, Raynaud D., PAD
Mainly arterioles, HR, edema, gingival hp. CI: HF
(Besylate, Maleate) Hypertension, angina
Drugs Acting on the Sympathetic NS
Mainly arterioles, HR, edema, long acting, DHP
italic = less important agent
NE = Norepinephrine
Alpha-Adrenoceptor Antagonists
Hypertension, opioid & nicotine withdraw
[ADHD],
(-methyl-dopa → +Coombs test)
a & c = Acute & Chronic
2,  cns sympathetic outflow,  NE release,
rebound HT; S: dry mouth, sedation, impotence.
-methyl-dopa → -methyl-NE (2- agonist, preg)
PHT = Postural hypotension
Phenoxybenzamine
Pheochromocytoma (a & c), HT (a & c)
1, irreversible, S: PHT, reflex tachycardia, long act.
Pheochromocytoma, acute HT,
[impotence]
, competitive, non-selective, S: PHT, reflex
tachycardia
Clonidine
(Catapres)
-Methyl-dopa
(Aldomet)
(Dibenzyline)
Phentolamine
(Regitine)
Tolazoline
Prazosin
(Priscoline)
[-azosin]
Terazosin
(Minipres) Benign prostate hypertrophy (BPH),
hypertension (a & c)
Doxazosin
Miscellaneous Agents
Fenoldopam
Reserpine
[ ] = Questionable therapeutic value
(Intropin) Shock to BP (renal vasodilatation ?, D,)
Dopamine
(Corlopam)
Guanethidine
Trimethapan
Mecamylamine
TCA = Tricyclic antidepressants
1 / 1 / D receptors, precursor to NE, I: MAOI
Acute hypertension (P), renal failure
D,A -receptor agonist, SE: HR, ocular P.,  K+
Hypertension (rarely used)
Reserpine: depletion NE ; Guaneth: NE release
(Arfonad)  BP, Ganglia-blockers (Nn-receptors,
(Inversine) competitive, many side effects)
Vasodilators
Hydralazine
1, competitive; no reflex tachycardia, first pass
effect S: PHT, nausea, drowsiness
Nn-antagonist, not oral; S: PHT, mydriasis
Nn-antagonist, active orally; S: PHT, mydriasis
Trade Name = (Italics)
(Apresoline)
Hypertension, HF (Bidil: hydralazine +
isosorbide dinitrate, Afro-Amercian)
Direct vasodilate, mainly arterioles TPR, combo Rx
S: reflex  SNS, flushing, palpitations, Lupus
Nitroprusside
(Nipride)
Minoxidil
Acute Hypertension crisis & HF
(Rogaine, Loniten) Hypertension, HF, baldness
Diazoxide
(Hyperstat)
Hypertensive crisis
 NO, cGMP, veins & arterioles TPR, iv only,
toxic oral S: as per hydralazine + cyanide toxicity
Open K+ channel, mainly arterioles TPR S: reflex
SNS, fluid retention, hypertrichosis. hyperglycemia
(CO, EDP, ejection volume <40%)
HEART FAILURE (HF, ‘Hormonal storm’)
Cardiac Glycosides
TI = Therapeutic index, CA = Catecholamines
Digoxin
(Lanoxicaps, Lanoxin) HF, SVT (arrhythmia), Important Rx
(use for HF, caution in women
interactions: Toxicity; : Ca++ blockers ie
verapamil; diuretics, quinidine, CAs, Amiod
ACEI/ARBs Lisinopril, Losartan (ARB)
Hypertension, HF
Positive Inotropic Agents
Dobutamine
(Dobutrex) HF (acute), cardiac stimulant
Milrinone, Amrinone
(Primacor, Inocor)
β-Blockers
Metoprolol, Carvedilol,
Bisoprolol
Vasodilators: Hydralazine, Bidil et al
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
pre/afterload, use HF, break neurohumoral cycle
PDE = Phosphodiesterase
1, iv, CO, tolerance, may cause angina
HF (chronic & acute)
Inh. PDE3, pre/afterloadcAMP, [mortality, oral]
Hypertension, HF (FDA approved 2002),
angina, arrhythmias etc
Hypertension, HF (see earlier notes)
afterload, use HF, CI: for HF if bronchospasm,
unstable HF, significant bradycardia (low reserve)
 preload,  afterload,  mortality, not primary Rx
Nesiritide; -naturiuretic peptide (Natrecor) Severe HF (Class IV, acute, iv)
Diuretics
Thiazides, Furosemide et al Hypertension, HF (see earlier notes)
ANGINA PECTORIS
cGMP  vasodilation,  pre- & afterload, 20 min
 pre- & afterload, congestion (furosemide) I: CG
CCBs=Calcium blockers, NO=Nitric oxide
(Nitrong, Nitrogard) Angina
CI: Sildendafil (Viagra)
Bioavailability
(10-20%),
Amyl & butyl
Isosorbide dinitrate & mononitrate
nitrites: Volatile, recreational abuse
β-blockers Propranolol etc (see earlier) Angina, HT, arrhythmia & others
NO, cGMP  vasodilation, preload coronary
flow, oral long duration, sublingual (fast), tolerance
(drug free time) S: headache, flushing, hypotension
 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
DI = Drug Interactions
Nitroglycerin
Peripheral Vascular Disease (PVD, PAD)
PAD, Prevent thrombosis
Inh. COX, Irrev. acetylation TXA2, platelet ag 
Pulmonary E, Prevent thrombosis
Inh. Vit. K.  clotting factors, CYP2C9, many DI
DVT, Pulmonary E, Prevent thrombosis
PAD, Prevent thrombosis
Act. antithrombin III, thrombocytopenia (HIT), T
1hr
nh. 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
nh. TXA synthase, TXA2, platelet ag.,
Abciximab
(Reopro)
Adjunct angioplasty, prevent thrombosis
MABnh. Platelet IIB/IIA receptors, platelet ag.,
Erectile dysfunction
Inh. PDE5, cGMP, require arousal, CI: nitrates
Acute MI, Pulmonary E. (clot-busters)
Activate plasminogendissolve clot, immediate use
SVT Supraventricular tachycardia
Aspirin
Warfarin
(Coumadin)
Heparin
Clopidogrel (Plavix),
Ticlopidine
Sildendafil, Vardenafil,
Streptokinase,
Tadalafil
Alteplase,
Reteplase
ANTIARRHYTHMIC AGENTS
Phase 0:Fast upstroke Phase 1:Partial repolarization
Phase 2:Plateau
Phase 3:Repolarization
Phase 4:Forward current
Nai+ open,
Na+ close, K+ open/close
Cai++ open, Ko+ leak
Ca++ close, Ko+ open
K+ close, Na+ Ca++ leak in
Sodium Channel blockers
APD = Action potential duration, CV = conduction velocity, RP = Refractory period
Quinidine
Procainamide
Lidocaine
(Cardioquin) Atrial arrhythmias, SVT
(Proneotyl) Ventricular arrhythmias
(Xylocaine) VT, VF (old DOC), iv, im
Phenytoin
Flecainide
(Dilantin) Arrhythmia, oral anticonvulsant
(Tambocor)
Ventricular arrhythmia
Class IA, Moderate block Phase 0, CV, QT, APD
S: M-, -receptor (TPR) block, diarrhea, nausea,
cardiac depression, Lupus I: Quinidine - CG
Class IB, Minimal block Phase 0, shorten Phase 3,
CV (least), phenytoin-gingival H. T: least toxicity
Class IC, Marked block Phase 0, CV (marked), no
chg APD T:  mortality, last resort agents
Class II, suppress Ph 4, SNS action on heart, CV
β-Blockers Esmolol, Sotalol (Cl. III) etc Angina, HT, arrhythmia (SVT) & others
Potassium Channel Blockers
Damaged tissue usually depolarized (CV), effects of antiarrhythmics more pronounced (all classes)
Amiodarone
(Cardarone)
(Dronedarone new agent, Bretylium)
CCBs
Verapamil, Diltiazem (not
Nifedipine) (see earlier notes)
Adenosine
(Adenocard)
Digoxin
Arrhythmia, VT (new DOC, multiple class
actions: I, II, III, IV)
Arrhythmia (SVT, acute + chronic),
hypertension, angina
Acute SVT (acts on adenosine-R)
(Lanoxicaps, Lanoxin) Atrial arrhythmia (stimulate Vagus N)
Class III, Ph 3, APD, RP; QT, Pulmon F, >25d,
cardiac dep, CYP3A4 sub/inh, I: CG, warfarin others
Class IV, CV, RP, increasing use, not for VT/VF,
constipation, rash, edema, gingival H CI: HF
A-R→ AC→ Open K+ channel; RP, CV; 15 secs
RP myocardium,RP purkinje fibers, AV CV
Potassium ions
Arrhythmia
Depress ectopic pacemakers, suppress Phase 4
Autonomic agents (EPI, atropine)
Arrhythmia (AV block)
Increase CV in AV node
DYSLIPIDEMIA (Lipid Lowering Agents)
Statins: HMG-CoA reductase inhibition
Atorvastatin, Simvastatin, Lovastatin
Resins: Bile acid reabsorption
Cholestyramine, Colestipol
Niacin: Inhibit VLDL release, Lipolysis
(also called Nicotinic A. or Vit B3)
Fibrates:Stimulate Lipoprotein Lipase, ↑PPARα
Clofibrate, Gemfibrozil, Fenofibrate
Inh. Cholesterol absorption: Ezetimibe
LDL, HDL, TGs
[-vastatin]
LDL, HDL, TGs
 Use, Liver toxicity, myopathy, rhabdomyolsis,  mylination CI:
pregnancy, children (? < 12 yrs).  LDL-rec→LDL uptake
Hate it, gritty taste, GI discomfort, constipation.  VLDL,  TGs,
 LDL-Rec., absp fat sol Vits (A, D, E, K), digoxin absp
LDL, HDL, TGs Flushed face (aspirin), GI discomfort, glucose intolerance, gout,
liver toxicity, ulcer, diabetes
LDL, HDL, TGs Nausea, skin rash, headache,  statin myopathy.
LDL synthesis (turnover), gallstones. CI: Gemfibrozil + statin
+ Statin combo (?) No major adverse effects noted, ↑cancer (?)
LDL, HDL