ANTIHYPERTENSIVE DRUGS

• PHYSIOLOGY OF BLOOD PRESSURE REGULATION

◦ blood pressure - force or tension of the blood pressing against the artery wall
◦ BP = Cardiac Output (CO) x Systemic Vascular Resistance (SVR)
‣ Cardiac Output = Heart rate (HR) x Stroke Volume (SV)
• Stroke Volume = Preload x Contractility
◦ Arterial BP is regulated by Baroreceptors (pressure sensitive neurons) - located in aortic arch
and carotid sinuses
‣ low BP --> baroreceptor send signals to adrenal medulla --> release of catecholamines -->
inc sympathetic activity --> activation of alpha- and beta-receptors
• activation in beta 1-receptors: increase HR, stroke volume --> inc CO --> inc BP
• activation of alpha 1-receptors on smooth muscles: constriction --> inc SVR --> inc BP
• inc renin --> inc angiotensin II --> constriction of blood vessels --> inc SVR --> inc BP
• inc renin --> inc angiotensin II --> inc aldosterone secretion --> inc Na and H2O
retention --> blood volume --> inc CO --> inc BP

• ANTIHYPERTENSIVE AGENTS
◦ Diuretics
‣ Loop Diuretics
• Furosemide
• reduces reabsorption of NaCl in the kidney --> significant diuresis --> less volume in
the vascular space --> less blood returns to the heart --> dec CO --> dec BP
• particularly in patients w/ volume based hypertension and CKD
‣ Thiazide Diuretics
• Hydrochlorothiazide
• reduces reabsorption of NaCl in the kidney but to a much smaller degree than loop
diuretics --> dec intravascular volume --> dec CO --> dec BP
• long term effects on blood volume are minimal and sustained anti-hypertensive
effects are produced by thiazide-induce vasodilation
‣ Potassium-Sparring Diuretics
• Triamterene and Spironolactone, Eplerenone
• inc diuresis by:
◦ interfering the Na-K exchange in the kidneys
◦ blocking the action of aldosterone
• often used in combination with Loop and Thiazide diuretics --> reduce loss of K
◦ that can occur with the use of this drug

SYMPATHOPLEGICS
◦ Centrally Acting Adrenergic Drugs (Sympatholytics)
‣ blocks sympathetic activity within the brain
‣ Clonidine
• selectively stimulates presynaptic alpha2-receptors --> negative feedback
mechanism --> dec catecholamine production and release --> dec SVR and CO --> dec
BP
‣ Methyldopa
• same mechanism as clonidine however, unlike clonidine, it is not an agonist itself
◦ must be converted first to its active metabolite, methylnorepinephrine
◦ Postganglionic Neuron Blockers
‣ Reserpine
• blocks VMAT
‣ Guanadrel
• blocks norepinephrine release
• depletes stores
◦ Alpha-1 Blockers "-zosin"
‣ Doxazosin and Prazosin
‣ blocks alpha1-receptors --> dec SVR --> dec BP
◦ Beta blockers "-olols"
 ‣ Selective
• Atenolol and Metoprolol
• blocks beta1-receptors --> dec CO --> dec BP
‣ Nonselective
• Labetalol and Carvedilol, Propanolol
• block alpha1-receptors and beta1-receptors --> dec CO and dec SVR --> dec BP
• inhibit beta1 receptors on the kidneys --> suppress release of renin --> suppress
formation of AT II --> suppress aldosterone secretion --> dec SVR --> dec BP

VASODILATORS (ORAL)
◦ Calcium Channel Blockers
‣ Dihydropyridines "-dipine"
• VASOSELECTIVE
• selectively inhibits L-type calcium channels in vascular smooth muscles
• in normal condition, when Ca2+ enters the smooth muscles-->contraction --> inc
SVR-->inc BP
• when dihydropyridine drugs blocks the entry of Ca2+ in the smooth muscles -->
contraction is inhibited --> dec VR --> dec BP
• amlodipine, felodipine, nicardipine, nifedipine
◦ amlodipine - longest half life
• side effects:
◦ systemic vasodilation - dizziness, headache, flushing, peripheral edema
◦ swelling of gums (gingival hyperplasia)
‣ Nondihydropyridines
• nonselective inhibitors of L-type Calcium channels
• not only capable of blocking the calcium channels on smooth muscles but also
calcium channels on cardiac cells, SA and AV node --> dec myocardial contractility,
HR and conduction (similar to beta blockers)
◦ AV node blockage
◦ decrease inotropy
◦ myocardial contractility
• this exhibit significant anti-arrhythmic properties
• do not significantly decrease CO d/t reflex tachycardia that occur as a result of
vasodilation
• Diltiazem, Verapamil
• side effects
◦ Excessive bradycardia
◦ cardiac conduction abnormality - LV depression
◦ Verapamil - least selective calcium channel blocker; can exert a significant
inhibition of calcium channels in the smooth muscles that lines the GI tract -->
constipation
◦ Direct-acting smooth muscle relaxants (Old Oral Vasodilators)
‣ Hydralazine
• unknown MOA
‣ Minoxidil
• stimulating opening of ATP-activated K channel in the smooth muscle --> membrane
stabilization --> vasoconstriction less likely --> dec peripheral resistance --> dec BP
• produce significant compensatory reflex tachycardia and renin release
• typically administered in combination with diuretics and beta blocker
• side effects: hair growth (topical application)
◦ more often used for treatment of baldness than hypertension

VASODILATORS (PARENTERAL)
◦ Fenoldopam
‣ selective dopamine-1 receptor agonist
• dopamine-1 receptors are located on smooth muscles on peripheral vasculature, as
well as renal, coronary, cerebral and mesenteric arteries
‣ by stimulating dopamine-1 receptors --> produces generalize arterial vasodilation --> dec
peripheral resistance --> dec BP
‣ inhibits tubular Na reabsorption --> natriuresis and diuresis
‣ d/t its rapid onset of action and short duration of action --> short term management of
severe hypertension (emergency)
◦ Sodium Nitroprusside and Nitroglycerin
‣ source of Nitric oxide (potent peripheral vasodilator)
‣ acute cardiac decompensation
 ‣ titratable
• short duration of action
• rapid onset of action
◦ Diazoxide
‣ K+ channel opener in smooth muscle, secretory cells
‣ hypertensive emergencies

DRUGS THAT AFFECTS RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS BLOCKERS)

◦ Renin Inhibitors
‣ Aliskerin
‣ selectively inhibits renin --> dec production of AT II
‣ renin
• responsible for conversion of angiotensinogen to angiotensin I
◦ ACE inhibitors (ACEIs) "-pril"
‣ benazepril, captopril, enalapril, lisinopril, quinapril*, ramipril
‣ selectively inhibits ACE --> dec production of AT II
‣ selectively inhibits ACE --> elevate production of bradykinin (peptide causing blood vessels
to dilate by stimulating the release of nitric oxide and prostacyclin) --> vasodilation
‣ Angiotensin Converting Enzyme (ACE)
• responsible for converting ATI to ATII
• it also inactivates bradykinin
◦ Angiotensin II Receptor Blockers (ARBs) "-sartans"
‣ candesartan, irbesartan, losartan, olmesartan, valsartan
‣ blocks the action of AT1 receptors
‣ Angiotensin II Receptors Type 1 (AT1 receptors)
• binding AT II to this receptors is responsible for most of the effects of AT II including
vasoconstriction and stimulation of aldosterone release
◦ either blocks the production of AT II or blocks the actions of AT1 receptor --> dec SVR but
without significant changes in CO
◦ reduces the effects of AT II on renal hemodynamics
‣ AT II constricts the efferent arteriole --> generating back pressure in the glomerulus -->
injury
‣ by reducing AT II --> improves renal blood flow --> reduce risk of renal injury
◦ side effects:
‣ hyperkalemia (d/t suppression of aldosterone release)
‣ ACEi: dry cough, and in rare cases, angioedema (life-threatening) - d/t inc bradykinin and
substance P

◦ Bosentan
‣ competitive antagonist of potent vasoconstrictor (Endothelin-1)
• acts on endothelin-A and B receptors located in pulmonary vascular cells
‣ by blocking the action of endothelin-1 on receptors --> vasodilation --> pulmonary
vascular resistance
‣ DOC for Pulmonary Hypertension

Pregnancy
• Methyldopa - maintenance dose
• Hydralazine (IV) -emergency cases
• Labetalol
• Contraindicated: ACEIs and ARBs