Chapter 21: Antihypertensive Drugs

Week 3

Hypertension

* Sustained, reproducible increase in blood pressure.


* Most common disease
* Can lead to cardiovascular problem, renal disease, blindness

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* Usually caused by a combination of several (multifactorial) abnormalities
* Genetic inheritance, psychological stress and environmental and dietary factors (increased salt and decreased potassium or calcium intake)
* Specific causes include:
* Renal artery constriction
* Coarctation of the aorta
* Pheochromocytoma
* Cushing's disease
* Primary aldosteronism
* Pts. in whom no specific cause of HTN can be found are said to have essential HTN (95%)
* Increase in BP with aging does not occur in populations with low daily sodium intakevhu

baroreceptor reflex

Short term

kidney

Long term

CO x TPR

BP

SV x HR

CO

BP

SV x HR x TPR

* Diet
* Stress
* Cigarette Smoking
* Alcohol

Possible mechanisms in essential HTN

Normal

120 - 129 systolic and <80 mmHg diastolic

Elevated

130-139 systolic or 80- 89 mmHg diastolic

Stage 1 HTN

≥140 systolic / ≥ 90 mmHg diastolic

Stage 2 HTN

Sympathetic nervous system

a final common pathway in mediating and perpetuating the hypertensive state

HR: (+) sympathetic discharge

TPR: norepinephrine and Angiotensin II

* Diuretics
* Sympatholytic Drugs
* Vasodilator
* ACE Inhibitor
* Calcium Channel Blocker
* Angiotensin Receptor Blocking Agents

Drug therapy

diuretics

* Increase formation and excretion of urine
* Increase renal excretion of water and sodium = decrease fluid volume

* Thiazide
* Loop diuretics
* Potassium sparing

Diuretics Classifications

Thiazide

act primarily on early portion of DCT of nephron and inhibit sodium reabsorption

Loop Diuretics

act primarily on ascending limb of loop of Henle; inhibit reabsorption of sodium and chloride thus prevents reabsorption of water

Potassium sparing

prevents secretion into the distal tubule

Thiazide diuretics

* Bendroflumethiazide (Naturetin)
* Chlorothiazide (Diuril)
* Chlorthalidone (Hygroton, Others)
* Hydrochlorothiazide (Esidrix, Others)
* Hydroflumethiazide (Diucardin, Saluron)
* Methyclothiazide (Enduron, Others)
* Metolazone (Diulo, Mykrox, Zaroxolyn)
* Polythiazide (Renese)
* Quinethazone (Hydromox)
* Trichlormethiazide (Metahydrin, Naqua)

Loop diuretics

* Bumetanide (bumex)
* Ethacrynic acid (edecrin)
* Furosemide (lasix, others)

Potassium sparing

* Amiloride (midamor)
* Spironolactone (aldactone)
* Triamterene (dyernium)

* Fluid Depletion
* Electrolyte Imbalance
* GI Disturbances

Diuretics adverse effects

* beta adrenergic blockers
* alpha adrenergic blockers
* presynaptic adrenergic neurotransmitter depletors
* central acting drugs
* ganglionic blockers

Sympatholytic drugs

beta adrenergic blockers

* Mainstay in the treatment of HTN
* Exerts primary effect on the heart
* Decrease HR and force of myocardial contraction
* General decrease in sympathetic tone

1. Central inhibitory effect on sympathetic activity
2. Influence renin release from kidneys and within CNS
3. Impair sympathetic activity in the ganglia or at presynaptic adrenergic terminals
4. Act by a combination of these

beta adrenergic blockers 4 theories

beta adrenergic blockers

* Acebutolol – Sectral
* Betaxolol - \*Kerlone
* Carteolol – Zebeta
* Esmolol – BreviBloc
* Metoprolol - Lopressor, \*Betaloc \*Neobloc
* Nebivolol - \*Nebicar
* Nadolol – Corgard
* Pindolol - Visken, \*Pyndale
* Propanolol - \*Inderal, \*Duranol
* Sotalol - \*Sotalex
* Timolol – Blocadren
* Atenolol - \*Ternomin, \*Cardioten, \*Tenorvas
* Bisoprolol - Zebeta, \*Concore
* Carvedilol - Cartrol, \*Cardipress, Dilapress
* Labetalol - Normodyne, Trandate
* Penbutolol - Levatol

* **Pindolol/Acebutolol** - partial agonists, intrinsic sympathomimetic activity
* **Labetalol/Propranolol** - membrane stabilizing activity
* **Labetalol and newer beta blockers** - peripheral vasodilation and cardiac beta blockade

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Some beta blockers are relatively selective for beta 1 receptors (cardioselective)

* Bronchoconstriction - nonselective
* Excessive Depression of HR and Myocardial Contractile
* Orthostatic Hypotension
* Depression
* Fatigue
* GI Disturbance
* Allergic Reaction

beta adrenergic blockers adverse effects

alpha adrenergic blockers

* Blocks alpha 1 adrenergic receptor on vascular smooth muscle
* Ability to improve blood lipid profiles
* Mild to moderate HTN

alpha adrenergic blockers

* Doxazosin - Cardura
* Prazosin - Minipress
* Terazosin - \*Hytrin, \*Lotencin, \*Hykor

* Orthostatic Hypotension
* GI Disturbance - Vomiting, Diarrhea

alpha adrenergic blockers adverse effects

presynaptic adrenergic neurotransmitter depletors (postganglionic sympathetic nerve terminal blockers)

Prevent normal physiologic release of norepinephrine from postganglionic sympathetic neurons

presynaptic adrenergic neurotransmitter depletors

* Guanadrel - Hylorel
* Guanethidine - Ismelin
* Reserpine

central acting drugs

* Inhibit sympathetic discharge from brainstem
* Similar to alpha 2 agonists - decrease sympathetic outflow

central acting drugs

* Clonidine - \*Catapres, \*Catapin
* Monoxidine and Rilmenidine - more selective for imidazoline receptors
* Guanabenz - Wytensin
* Guanfacine - Tenex
* Methyldopa - \*Aldomet, \*Dopamet

* Dry mouth
* Dizziness
* Drowsiness

central acting drugs side effects

ganglionic blockers

* Most of such drugs are no longer available clinically because of intolerable toxicities related to their primary action
* Block synaptic transmission at autonomic ganglia
* Decrease sympathetic activity
* Nicotinic Cholinergic Antagonists - between Pre & Postsynaptic neurons of both divisions

ganglionic blockers

HTN Crisis

ganglionic blockers

Mecamylamine – Inversine

* Dry Mouth
* GI Discomfort
* Constipation
* Urinary Retention
* Visual Disturbances like Precipitation of Glaucoma, Blurred Vision
* Excessive Orthostatic Hypotension
* Sexual Dysfunction (Sympathoplegia)
* Neuromuscular Blockade

ganglionic blockers side effects

vasodilators

* Vasodilates peripheral vasculature
* Inhibits smooth muscle contraction due to increased 2nd messengers (cyclic GMP)

vasodilators

* Diazoxide – Hyperstat IV
* Fenoldopam - Corlopam
* Hydralazine - \*Apresoline, \*Aprezin
* Minoxidil - Loniten
* Nitroprusside - Nitropress

* Reflex Tachycardia
* Dizziness
* Postural Hypotension
* Weakness
* Nausea
* Fluid Retention
* Headache

vasodilators side effects

angiotensin converting enzyme inhibitors

Inhibits enzyme that converts angiotensin 1 to angiotensin 2 (Renin-Angiotensin System)

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ADVANTAGES:

* Lower incidence of cardiovascular side effects
* No reflex •tachycardia and orthostatic hypotension
* Prevents hypertrophy of heart and vasculature (animal)

USE:

* Mild to moderate HTN, may be used alone or in combination.

angiotensin converting enzyme inhibitors

* Benazepril - Lotensin, \*Cibacen
* \*Cilazapril - \*Vascace
* Captopril -\*Capoten, \*Ace-Bloc
* \*Delapril - \*Cupressin
* Enalapril - Vasotec, \*Acebitor, \*Renitec
* Fosinopril - Monopril, \*Bpnorm
* \*Imidapril - \*Norten
* Lisinopril - Prinivil, \*Zestril
* Moexipril - Univasc
* Perindopril - Aceon, \*Coversyl
* Quinapril - \*Accupril
* Ramipril - Altace, \*Ramipro, \*Tritace
* Trandolapril - Mavik

* Allergic Reaction
* Rash
* GI Discomfort
* Dizziness
* Chest Pain
* Persistent Dry Cough

angiotensin converting enzyme inhibitors side effects

angiotensin receptor blockers

Blocks angiotensin II type 1 (AT1) receptor

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ADVANTAGES:

* No effect on bradykinin metabolism and are therefore more selective blockers of angiotensin effects
* Have the potential for more complete inhibition of angiotensin action
* Provide benefits similar to those of ACE inhibitors in patients with heart failure and chronic kidney disease.

angiotensin receptor blockers

* Candesartan - Atacand, \*Candelong
* Eprosartan - \*Teveten
* Irbesartan - Avapro, \*Aprovel, \*Izart
* Losartan - \*Cozaar, \*Angisartan
* Olmesartan - Benicar, \*Olmetec, \*Olmezar
* Telmisartan - \* Micardis, 8pritor
* Valsartan - \*Diovan

* Similar to those of ACE inhibitors including the hazard of use during pregnancy
* Cough and angioedema can occur but are less common

angiotensin receptor blockers adverse effects

calcium channel blockers

* Blocks calcium entry into vascular smooth muscle cell
* Decreased vascular resistance
* Tends to decrease HR and myocardial contractile force

calcium channel blockers

* Amlodipine - Amvaz, \*Norvasc, \*Amlodine
* Diltiazem - Cardizem, \*Angiozem, \*Dilzem
* Felodipine - \*Plendil, \*Versant
* Isradipine - Dynacirc, \*Icaz SRO
* Nicardipine - Cardene, \*Cardepine
* Nisoldipine - Sular
* Nifedipine- \*Adalat, Procardia, \*Calcibloc
* Verapamil - Calan, \*Isoptin
* \*Benidipine - \*Coniel
* \*Barnidipine - \*Hypoca
* \*Lacidipine - \*Lacipil
* Manidipine - \*Caldine

* Excessive Vasodilation
* Orthostatic Hypotension
* Reflex Tachycardia
* Abnormal HR
* Dizziness
* Headache
* Nausea

calcium channel blockers adverse effects

step care approach

1. Diuretic, Beta blocker, ACE inhibitor, Ca channel blocker
2. Second agent


1. Second group - central acting, alpha 1 blocker, vasodilator, presynaptic inhibitor
3. 3 different agents from different classes
4. Fourth drug from another class

nonpharmacologic treatment

* Sodium Restriction
* Low Fat Diet
* Diet High in Fish Oil
* Reduce Weight
* Reduce Alcohol Consumption
* Quit Smoking
* Behavior Modification/Stress Management