12.01.3 Vasodilators for Hypertension

Some drugs cause vasodilation, and some drugs reverse vasoconstriction to effectively cause vasodilation, and I refer to both of these mechanisms as vasodilation.

Three groups of vasodilators are used in the treatment of hypertension, inhibitors of the renin-angiotensin system (angiotensin converting enzyme inhibitors and AT1 receptor antagonists), Ca2+ channel blockers, and α1-adrenoceptor antagonists.

Angiotensin II is a potent vasoconstrictor, stimulates hypertrophy, and stimulates aldosterone secretion.  Aldosterone causes salt and water retention, and fibrosis (the laying down of collagen in the heart), which all worsens the hypertension.  Angiotensin converting enzyme has a key role in the renin-angiotensin-aldosterone system. It is involved in the conversion of angiotensin I, which is an inactive decapeptide to angiotensin II, the active octapeptide.  Angiotensin converting enzyme is also involved in the breakdown of bradykinin.  Bradykinin is a potent vasodilator, which is broken down in the presence of angiotensin converting enzymes to inactive fragments.

When angiotensin converting enzyme is inhibited with an angiotensin converting enzyme (ACE) inhibitor, there are decreased levels of angiotensin II, and aldosterone (Figure 12.1.3).

Figure 12.1.3 ACE inhibition (Copyright QUT, Sheila Doggrell).

As angiotensin II and aldosterone both increase blood pressure, lowering their levels, will decrease blood pressure.  ACE inhibitors will also decrease the breakdown of bradykinin increasing the levels of this vasodilator, which will also contribute to the decrease in blood pressure observed with ACE inhibitors.

The ACE inhibitors all have names that end in PRIL, such as enalapril.  The prils are used as vasodilators in the treatment of hypertension.   Enalapril is available alone in a tablet or in combination with hydrochlorothiazide.  Enalapril is metabolised in the gut to the ACE inhibitor enalaprilat, which has a 60% bioavailability after oral administration.  Enalaprilat will decrease the levels of angiotensin II (vasoconstrictor), decrease levels of aldosterone (Na+ and water retention) and increase the levels of the vasodilator bradykinin.  All of these effects contribute to the ability of enalapril to decrease blood pressure.

Enalaprilat is predominantly eliminated by kidneys, which means the dose needs to be reduced in renal impairment to avoid increased levels and excessive vasodilation.  The prils can adversely cause a dry cough, which is quite common, and angiodema (rare).  Both of these conditions are probably due to the accumulation of bradykinin that has many effects other than vasodilation.  These adverse effects do not occur with the angiotensin II receptor antagonists, as these have no effect on bradykinin levels.  People who cannot tolerate ACE inhibitors are often transferred to AT1 receptor antagonists, which do not alter the levels of bradykinin.

The majority of the cardiovascular effects of angiotensin II are mediated by AT1-receptors.  AT1-receptor antagonists have names ending in sartan.  The sartans, such as candesartan, inhibit effects mediated by AT1 receptors to decrease vasoconstriction (effectively vasodilation) decrease hypertrophy, and decrease aldosterone secretion and the effects of aldosterone (Figure 12.1.4).

Figure 12.1.4 AT1-receptor antagonism (Copyright QUT, Sheila Doggrell) 

Candesartan is available alone or in combination with hydrochlorothiazide (thiazide diuretic).  The adverse effects with ACE inhibitors of dry cough and angiodema (rare) do not occur with AT-1 antagonists.

By reducing blood volume, diuretics stimulate the renin-angiotensin system.  This sensitizes (makes the effects bigger) the patients to ACE inhibitors and AT-1 antagonists, making the combination of a diuretic and an ACE inhibitor or AT-1 antagonist more effective at reducing blood pressure than either a diuretic alone, or an angiotensin II inhibitor alone.

The ACE inhibitors and the AT-1 receptor antagonist (Angiotensin Receptor Antagonist, ARBs) are contraindicated in pregnancy.  Hypertension is quite common in pregnancy, and the ACE inhibitors and ARBS must not be used to treat any hypertension associated with pregnancy.  If they are used in first semester, the ACE inhibitors and ARBs cause major congenital malformations, which are defects/damage to developing fetus.  This is probably because angiotensin II has a major role in fetal development.  If the ACE inhibitors or ARBs are uses in second and third semester, they cause fetal renal dysfunction and oligohydramnios (deficiency in amniotic fluid), and can lead to fetal death.

The second group of vasodilators used in the treatment of hypertension are the Ca2+ entry blockers.  Ca2+ entry blockers are also known as Ca2+channel blockers, and Ca2+ antagonists. There are subtypes of Ca2+ channels; L-, N-, P/Q-, R- and T-type (Figure 12.1.5).  The Ca2+ channels on the cardiovascular system are L-type, with Cav1.2a being predominantly found on heart muscle and the Cav1.2b being predominantly found on blood vessels.  We have drugs that select for the Cav1.2 subtypes, and those that select for Cav1.2a will act predominantly on the heart and those that select for Cav1.2b will act predominantly on the blood vessels.

Figure 12.1.5 Subtypes of Ca2+ channels (Copyright QUT, Sheila Doggrell) 

Regardless of what is contracting the blood vessel, whether it is depolarization or noradrenaline acting at α-adrenoceptors or 5-HT acting at 5-HT2-receptors, contraction of vascular smooth muscle requires Ca2+ entry into cells through Ca2+ channels (Figure 12.1.6).  This makes Ca2+ channel blockers are effective against all vasoconstrictors.


Figure 12.1.6 Ca2+ channels and vasoconstriction (Copyright QUT, Sheila Doggrell) 

An example of a calcium channels blocker is amlodopine.  Amlodopine has a greater effect on the blood vessels than the heart, and thus causes vasodilation with little effect on the heart.  Amlodopine is available as a once a day preparation.  Amlodopine is used in the treatment of essential hypertension.  With calcium channel blockers, the most common side effects are related are extensions of the therapeutic effect to excessive vasodilation causing headache, flushing, and dizziness.

The third class of vasodilator used in the treatment of hypertension are the α1-adrenoceptor antagonists, such as prazosin.  On activation of the sympathetic nervous system, noradrenaline is released and stimulates α1-adrenoceptors on blood vessels to cause vasoconstriction.  Prazosin will bind to the α1-adrenoceptor to reduce the binding of noradrenaline, and the resulting vasoconstriction, effectively causing vasodilation and reducing blood pressure.  α1-Adrenoceptor antagonists can only be used to cause small decreases in blood pressure, as excessive vasodilation leads to adverse effects.  Presently, prazosin is occasionally used in combination with other anti-hypertensive drugs.  For instance, if the combination of a diuretic and a β-blocker fails to control blood pressure, an α1-adrenoceptor antagonist may be added.
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Pharmacology InOneSemester,
Mar 24, 2015, 9:22 PM
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