CLINICAL PHARMACOLOGY REVIEWER

CARDIOVASCULAR DRUGS

I. HYPERTENSION
 Definition: A sustained systolic blood pressure (SBP) of greater than 140mmHg or a
sustained diastolic blood pressure (DBP) of greater than 90 mmHg
Blood pressure classification according to JNC VII
SBP mmHg DBP mmHg

Normal <120 <80

Prehypertensive 120-139 80-89
Stage 1 140-159 90-99
hypertension
Stage 2 ≥ 160 ≥ 100
hypertension

BLOOD PRESSURE = Cardiac output x Total Peripheral Resistance

CO = Stroke volume x Heart rate
Stroke volume (SV) is affected by the preload, afterload, contractility

Relationship of each determinant of BP:

 High cardiac output = increase BP
 Increase TPR (Vasoconstriction)= increase BP
 Decrease TPR (Vasodilation)= decrease BP
 Increase stroke volume and heart rate = increase CO and increase BP
 Increase preload= increase SV
 Good myocardial contractility= increase SV
 Increase afterload= decrease stroke volume

Stroke volume – volume of blood pumped out of the left ventricle of the heart during
each systolic cardiac contraction
Preload – initial stretching of the cardiac myocytes prior to contraction; it is the volume that
returns to heart
Afterload – pressure that the heart must go against to eject blood during systole
Contractility – innate ability of the heart muscle to contract

To lower the BP, drugs will:

 Decrease the TPR (vasodilation)
 Decrease the cardiac output
 Decrease heart rate
  Decrease stroke volume, preload, contractility
 Decrease afterload (vasodilation)

Anti-hypertensive drugs
a. Centrally acting sympatholytics
o Methyldopa (false neurotransmitter)
o Clonidine (alpha 2 agonist)
o Guanabenz
o Guanfacine
 Mechanism of action: reduce sympathetic outflow from vasopressor centers in the
brainstem but allow these centers to retain their sensitivity to baroreceptors
 Side effects:
o Methyldopa: Positive coomb’s test, lactation, extrapyramidal symptoms
o Clonidine: hypertensive crisis secondary to abrupt withdrawal of the drug
o Other: CNS effects such as depression, sedation and lassitude
b. Ganglion-blocking agents
o Trimetaphan and Mecamylamine
 Mechanism of action: Competitively block nicotinic cholinoceptors on postganglionic
neurons in both sympathetic and parasympathetic ganglia
 Side effects:
o Sympathetic: orthostatic hypotension
o Parasympathetic: Constipation, urinary retention, precipitation of glaucoma,
Dry mouth (xerostomia)
c. ADRENERGIC NEURON-BLOCKING AGENTS
o Guanethidine, Guanadrel, Reserpine
 Mechanism of action: Lower blood pressure by preventing normal physiologic release of
norepinephrine from postganglionic sympathetic neurons
 RESERPINE
o An alkaloid extracted from the roots of an Indian plant, Rauwolfia serpentine
 Mechanism of action:
o Blocks the ability of aminergic transmitter vesicle to take up and store biogenic
amines/catecholamine interfering with an uptake mechanisms that depends on
Mg2+ and ATP
NOTE: PLEASE MEMORIZE THIS

d. Alpha-1 adrenergic antagonists/blocking agents

o Prazosin, Doxazosin, Terazosin
 Mechanism of actions:
o Blocks α1-receptors in vascular smooth muscle (arterioles and venules)
o In effect:
 Decrease peripheral vascular resistance or total peripheral resistance
(TPR)
 Dilates both resistance and capacitance vessels (vasodilation)---- results
to reduce in blood pressure
 Side effects: First dose phenomenon
o Give this drug at bedtime
 Other alpha 1 adrenergic blockers are used for benign prostatic hyperplasia
o Tamsulosin, Silodosin, Alfuzosin, Bunazosin
 Non-selective alpha blockers: Phenoxybenxamine and Phentolamine
o Useful in the treatment and diagnosis of pheochromocytoma
o Phentolamine can be used together with Propranolol to treat clonidine
withdrawal syndrome
 Selective alpha 2 blocker: Yohimbine
e. Beta-adrenergic blocking agents (end with “olol”)
 o Non-selective (Blocks both B1 and B2 receptors)
o Nadolol
o Penbutolol
o Pindolol
o Propranolol (prototype)
o Timolol (ophthalmic preparation)
o Sotalol
o Carteolol
o Non-selective (block B1 and alpha 1 receptors)
o Labetalol and Carvedilol
o Selective
o Acebutolol
o Atenolol
o Bisoprolol
o Metoprolol
o Betaxolol
o Nebivolol ( may also increase production of NO)
o Esmolol
o Intrinsic sympathetic activity
o Acebutolol
o Carteolol
o Penbutolol
o Pindolol

 Mechanism of action:
o Reduce blood pressure primarily by decreasing cardiac output
o Decrease sympathetic outflow from the CNS
o Inhibit the release of renin in the kidney

f. Vasodilators
o Hydralazine
o Minoxidil
o Nitroprusside
o Diazoxide
o Fenoldopam
o Calcium channel blockers
 Hydralazine:
o Combines with receptors in the endothelium of arterioles -----NO release------
relaxation of vascular smooth muscle------fall in BP
o Side effects: resembles lupus erythematosus
 Minoxidil
o Side effect: hirsutism
 Nitroprusside:
o Can be given during hypertensive emergency
o Red blood cells convert nitroprusside to nitric oxide---- vasodilation----- decrease
BP
o Side effect: cyanide toxicity and methemoglobinemia
 Antidote: sodium thiosulfate and hydroxycobalamin
o Diazoxide:
 similar to thiazide diuretic
 Inhibits insulin release from the pancreas
 Used to treat hypoglycemia secondary to insulinoma
o Fenoldopam
o Used for hypertensive emergencies and postoperative hypertension
o Acts primarily as an agonist of dopamine D1 receptors resulting in
dilation of peripheral arteries and natriuresis
g. CALCIUM CHANNEL BLOCKERS
 Mechanism of action:
o Increase the time that Ca2+ channels (L channels) are closed
 Blocks both activated and inactivated L-type calcium channels
o Relaxation of the arterial smooth muscle but not much effect on venous
smooth muscle
o Significant reduction in afterload (arteries) but not preload (venous)
o
o Non-dihydropyridine (can cause vasodilation but in lesser degree compared to
dihyrdropyridine CCBs)
o Verapamil
o Diltiazem
 Also used as anti-arrhythmic drugs (Class IV)
o It lowers the heart rate
o Use in supraventricular tachycardia
o It can suppress both early and delayed after depolarization
o It can induce heart block (AV block)
o Other side effect: constipation (Verapamil)
o Take note: do not use in patient with acute heart failure because of it can
depress contractility of the heart
o Dihydropyridine (end in “dipine’)- more pronounced vasodilation, no effect on the
conduction, contractility and chronotropic activity of the heart
o Amlodipine (has highest bioavailability and longest elimination half-life)
o Felodipine
o Nifedipine (protoype)
o Lecarnidipine
o Isradipine
o Nicardipine (given for hypertensive emergencies)
o Nisoldipine
  Side effects: peripheral edema, gingival hyperplasia, hypotension
h. Angiontensin converting enzyme inhibitors (end with “pril”
o Captopril
o Enalapril
o Linisinopril, Fosinopril, Perindopril, Quinapril, Ramipril, Benazepril

 Mechanism of action:
o Vasodilation both arterial and venous
 Reduce arterial and venous pressure
 Reduce preload and afterload
o Decrease blood volume (decrease levels of aldosterone)
o Inhibit cardiac and vascular hypertrophy
o Depress sympathetic activity
 Side effect:
o cough and angioedema
 secondary to bradykinin and substance P release
o hyperkalemia
 Be careful in patient with bilateral renal artery stenosis
i. Angiotensin receptor blockers (ends with “sartan”)
o Losartan, Telmisartan, Candesartan, Irbesartan
o Valsartan, Olmesartan, Eprosartan
 Mechanism of action:
o Produce arteriolar and venous dilation and block aldosterone secretion thus
lowering blood pressure and decreasing salt and water retention
 Does not cause cough and angioedema
j. Diuretics

 Carbonic anhydrase inhibitors

o Acetazolamide:
 Site of action: proximal tubule (majority) and also acts at
collecting tubule
 MOA: blocks the carbonic anhydrase enzyme responsible for
dissociation of carbonic acid to water and carbon dioxide
 Uses:
  Treatment of Glaucoma (most common indication)
o Reduction of aqueous humor formation
o Decrease intraocular pressure
 Urinary alkalinization
 Correction of Metabolic alkalosis
 Prevention of acute mountain sickness
 Can be used for aspirin toxicity (together with NaHCO3)
 Side effects: hypokalemia, metabolic acidosis, nephrolithiasis
(increase phosphate urinary excretion)
 Loop diuretics
o Ethacrynic acid, Furosemide, Torsemide, Bumetanide
o Site of action: Thick ascending limb of Loop of Henle
o Mechanism of action: inhibits the Na/K+/2Cl- cotransporter
o Highest anti-diuretic effect
o Uses:
 Acute CHF, acute pulmonary edema
 Edema associated with renal and liver disease, heart failure
 Treatment of hyperkalemia
 Hypertension
 Acute hypercalcemia
 Reduction of intracranial pressure (same as mannitol)
o Side effects:
o Hypokalemia
o Metabolic alkalosis
o Ototoxicity
o Hypomagnesemia
o hyperuricemia
 Thiazide diuretics
o Hydrochlorothiazide, Indapamide
o Metolazone (
o Site of action: distal convoluted tubule
o MOA: inhibits NaCl- cotransporter
o Uses:
 Adjunctive therapy for edema associated with CHF, cirrhosis,
corticosteroid, and estrogen therapy
 Treatment of hypertension (part of maintenance)
 Nephrolithiasis due to idiopathic hypercalciuria
 Nephrogenic diabetes insipidus
o Side effects:
 Metabolic alkalosis
 Hyperuricemia
 Hyperlipidemia
 Hyperglycemia
  Impaired pancreatic release of insulin; decrease tissue
utilization of glucose
 Hypokalemia

 Potassium sparing diuretics

o Spironolactone, Eplerenone: blocks the aldosterone in binding to
aldosterone receptor located at the basolateral membrane of principal
cell of collecting ducts
o Amiloride and Triamterene: blocks the ENaC located at the apical
membrane of principal cells of collecting duct
o Site of action: principal cells of collecting ducts
o Uses:
 Most useful in mineralocorticoid excess due to either primary
hypersecretion (Conn’s syndrome), ectopic ACTH production
 Secondary aldosteronism
 Heart failure
 Hepatic cirrhosis
 Nephrotic syndrome
o Side effects:
o Hyperkalemia, Metabolic acidosis
 Inhibit H+ secretion in parallel with K+ secretion
o Spironolactone: Gynecomastia, impotence, and benign prostatic
o Triamterene together with indomethacin
 Kidney stones
o Eplerenone: more potent than spironolactone, no effects on androgen
therefore does not present with gynecomastia/impotence
 Osmotic diuretics
o Mannitol
 Primarily indicated for the management of increase intracranial
pressure

o Side effects:
 Acute kidney injury, hypernatremia: if volume status is not
carefully monitored
 Expansion of extracellular volume
o Urea
o Glycerine

CONGETIVE HEART FAILURE

 Potential Therapeutic Targets in Heart Failure
o Heart rate
o Preload
o Afterload
 o Contractility
 Levosimendan
o increase calcium sensitivity and inhibit phosphodiesterase enzyme
 Digoxin
o Inhibit Na/K/ATPase
o Hypokalemia: increase toxicity
o Hyperkalemia: decrease toxicity
o Mg2+
o Hypomagnesemia: increases toxicity
o Ca2+
o Hypercalcemia: increases toxicity

 Phosphodiesterase enzyme inhibitor: Milrinone and Inamrinone

o inhibition of type 3phosphodiesterase
 increase intracellular cAMP
o increase Ca2+ entry through L type Ca channels
 inhibition of Ca2+ sequestration by SR
 Diuretics:
o Spironolactone:
 Lowers the morbidity and mortality of patients with heart failure
 ACE inhibitors/ARB blockers
 Vasodilators (nitrates)
 Beta blockers

ANGINA/MYOCARDIAL INFARCTION
 Definition:
 Stable angina:
o Is characterized by chest or arm discomfort that may not be described as pain
but is reproducibly associated with physical exertion or stress
o Caused by the reduction of the coronary perfusion due to a fixed obstruction
produced by coronary atherosclerosis
o Relieved within 5-10 minutes by rest and/or sublingual nitroglycerin
 Prinzmetal angina
o Transient spasm of localized portions of coronary artery associated with
underlying atheromas
o Attacks are unrelated to physical activity, heart rate or blood pressure
o Responds promptly to coronary vasodilators such as nitroglycerin and calcium-
channel blockers (dihydropyridines are more effective than non-dihydropyridine)

 Unstable angina
o Angina pectoris or equivalent ischemic discomfort with at least one of the three
features
o Occurs at rest (or with minimal exertion) usually lasting > 10 minutes
 o Severe and of new onset
o Occurs with a crescendo pattern
o Symptoms are not relieved by rest of nitroglycerin
o Requires hospital admission and more aggressive therapy to prevent death and
progression to myocardial infarction
Take note: if the chest pain/angina worsens inspite of giving nitrates, bring patient to the
nearest hospital for further evaluation and management.

ANTI-ARRHYTHMIC DRUGS
 Class I: not all prolong the action potential/ERP
o Class IA: prolong action potential
 QUINIDINE, PROCAINAMIDE, DISOPYRAMIDE
o Class IB: decrease action potential and decrease ERP; They suppress arrhythmias
caused by abnormal automaticity (reduces abnormal automaticity)
 LIDOCAINE
 First drug of choice for ventricular tachycardia
 MEXILETINE
 Oral analogue of Lidocaine
 PHENYTOIN
 Also an anticonvulsant drug
 Tocainide
o Class IC: has minor effects on action potential and ERP
 FLECAINIDE, PROPAFENONE, MORICIZINE
 Class II: Beta-blocker
o Sotalol: has both class II and class III anti-arrhythmic effects
 Class III: prolong both the action potential and effective refractory period (ERP)
o MOA: inhibits K+ channels
o Bretylium
o Amiodarone:
 Can cause pulmonary fibrosis
 Hypo/hyperthyroidism
o Sotalol

 Class IV: Calcium channel blocker (non-dihydropyridines)

Adenosine:
 Naturally occurring purine nucleoside that forms from the breakdown of adenosine
triphosphate
 Activates P1 purinergic receptors (A1) that coupled to K channels
 Most effective for atrial tachycardia, Paroxysmal supraventricular tachycardia

SUMMARY:
• Premature atrial, nodal or ventricular depolarization:
 • No drug therapy indicated
• Atrial fibrillation, flutter, and PSVT:
• AV nodal blockers to control ventricular response:
• Adenosine, Class II, Class IV, digoxin
• Note: AV nodal blockers may be harmful in WPW syndrome
• Depending on arrhythmia: Class III, Class IA, Class 1C
• Ventricular tachycardia (w/ remote MI):
• Amiodarone, Class III, Class I
• Ventricular fibrillation:
• Lidocaine, amiodarone, Class III, Class I
• Torsades de pointes:
• Acute: Magnesium, isoproterenol
• Chronic: Class II