Calcium Channel Blockers

These drugs have a direct dose-related effect on three separate functions of the heart (conduction, contraction, and inotropy), and on peripheral and coronary vascular tone. When used to treat high blood pressure, the major effect of these drugs is arterial vasodilation by blockade of Ca ²⁺ influx through L-type voltage-gated Ca ²⁺ channels in the smooth muscle cells of resistance vessels. They also reduce the increase in intracellular Ca ²⁺ in response to membrane depolarization and the secondary Ca ²⁺ -induced Ca ²⁺ release from intracellular stores. Some calcium channel blockers also reduce heart rate and myocardial contractility, which leads to decreased cardiac output and blood pressure.

There are 3 classes of calcium channel blockers. Difference in subunit structure of Ca ²⁺ channels in vascular and cardiac tissues might explain the different selectivity of the drugs. The dihydropyridines act mainly on vascular smooth muscle of resistance vessels, while the nondihydropyridines act on the myocardium. All 3 classes act on voltage-gated Ca ²⁺ channels that are made up of 5 subunits (α ₁ , α ₂ , β, γ, and δ). The α ₂ and δ subunit dimer and γ subunit are transmembrane, while the β unit is located intracellularly. The α ₁ subunit forms the transmembrane ion channel.

Dihydropyridines (e.g., nifedipine and nicardipine) bind to the extracellular domain of the L-type voltage-gated Ca ²⁺ channel (Ca _V 1) in the cell membrane, thus inhibiting Ca ²⁺ influx. These drugs primarily affect resistance vessels with minimal effects on veins owing to the low density of L-type Ca ²⁺ channels in capacitance vessels.

Phenylalkylamines (e.g., verapamil) act mainly on the heart, where inhibition of voltage-gated Ca ²⁺ channels is frequency dependent. The phenylalkylamines probably enter the cell and bind internally to produce their effects.

Benzothiazepines (e.g., diltiazem) bind on the extracellular side of the L-type channel. Their effects are greater on vascular compared with cardiac smooth muscle.

β Blockers

There are at least 3 distinct subtypes of β receptors (β ₁ , β ₂ , and β ₃ ), each of which has different tissue distributions. Both β ₁ and β ₂ agonists mediate their cellular effects through increases in cyclic adenosine monophosphate (cAMP). β receptors are G protein–coupled receptors that traverse the lipid cell membrane 7 times. The N-terminal end of the protein is extracellular and the C-terminal end is intracellular. The region conferring β-receptor coupling is thought to lie in the third cytoplasmic loop between the fifth and sixth transmembrane segments (for further details on this receptor, see Chapter 1 ).

β ₁ receptors are present mainly in heart muscle. The ligand–receptor complex is coupled to a Gs protein, which, in turn, activates adenylyl cyclase to produce cAMP. The cAMP activates protein kinase A, leading to enhanced influx of Ca ²⁺ and, in turn, muscle contraction.

β ₂ receptors exist in heart muscle (hence the rationale for use of salbutamol in some patients with low-output states). However, they are more abundant in bronchial and peripheral vascular smooth muscle, where they lead to bronchodilation and vasodilation, respectively (see Chapter 30 ).

β ₃ receptors are present in adipose tissue and heart muscle. In contrast to β ₁ and β ₂ adrenoceptors, activation of β ₃ leads to a decrease in inotropic state of the myocardium via a Gi protein–dependent pathway. Thus, as well as having an effect on thermogenesis, β ₃ activation can lead to cardiodepressant effects.

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Antagonists

Renin is a protease synthesized in the kidney that catalyzes the production of angiotensin I from angiotensinogen (a 225 amino acid prohormone). Angiotensin-converting enzyme (ACE) then biotransforms angiotensin I to angiotensin II—the latter being a vasoconstrictor through action at angiotensin receptors. The molecular mechanism of action for angiotensin II is through coupling to the phospholipase C Gq protein–IP ₃ transduction pathway. Angiotensin II also affects norepinephrine kinetics through facilitation of its release and prevention of its reuptake at sympathetic nerve terminals. The renin–angiotensin pathway can therefore be interrupted at two separate sites (both leading to vasodilation): direct inhibition of ACE and angiotensin receptor antagonism ( Fig. 26.2 ).

Mechanisms of action of angiotensin-converting enzyme inhibitors with inhibition of conversion of angiotensin I to angiotensin II, and inhibition of the breakdown of bradykinin to inactive peptides.

ACE inhibition occurs both in plasma and in the vascular endothelium. Inhibition also reverses arteriolar hypertrophy that occurs in hypertension and reduces left ventricular hypertrophy. ACE inhibitors decrease conversion of angiotensin I to angiotensin II, thereby reducing vasoconstrictor effects, aldosterone secretion, and sympathetic activation (see Chapter 40 ). Angiotensin II acts on AT ₁ receptors via Gq to activate phospholipase C. This has the effect of increasing intracellular diacyl glycerol (DAG) and IP ₃ , which increase Ca ²⁺ release from the sarcoplasmic reticulum (SR) to cause vasoconstriction of the efferent arteriole. Stimulation of the AT ₂ receptor leads to smooth muscle proliferation and ventricular remodeling ( Fig. 26.3 ).

Mechanism of action of angiotensin II receptor blockers (at the AT ₁ and AT ₂ angiotensin receptors). DAG, Diacylglycerol; IP ₃ , inositol trisphosphate; PLC, phospholipase C.

Both ACE inhibitors and AT receptor antagonists produce arterial vasodilation by limiting the direct effects of angiotensin II on vascular smooth muscle and minimizing its ability to increase sympathetic vascular tone. Their action is accompanied by an increase in parasympathetic tone. They also decrease the effect of aldosterone on the distal convoluted tubule of the nephron, thus promoting salt and water loss. They also block breakdown of bradykinin, which, in turn, contributes to the vasodilator effects of the drugs.

ACE inhibitors prevent the breakdown of kinins; the increased concentration of bradykinin is probably responsible for the unwanted side effects of cough and allergic reactions. Other side effects of ACE inhibitors include diarrhea. On the other hand, the angiotensin receptor antagonists prevent the vasoconstrictor effects of angiotensin II without affecting ACE activity. Thus, in contrast to ACE inhibitors, they do not affect kinin production (hence, cough is not a prominent side effect of these drugs). These drugs act as selective blockers at the AT ₁ receptors, with no effect on AT ₂ receptors.

Diuretics

The action of diuretics to reduce blood pressure is twofold. First, they cause an initial decrease in intravascular volume, although compensatory mechanisms are activated and this effect is reduced over time. They have a secondary mechanism to reduce blood pressure by direct arterial vasodilation. The exact mechanism involved is not clear but might be through a decrease in Ca ²⁺ entry into smooth muscle cells and through stimulating local vasodilator prostaglandin formation. Although the decrease in intravascular volume and total body Na ⁺ occurs within weeks of the start of diuretic therapy, an increase in renin release causes them to return to normal. The antihypertensive effects of diuretics are not just related to their effects on Na ⁺ and water balance, because more effective diuretic agents (e.g., furosemide) are not very effective hypotensive agents.

There are 3 main classes of diuretics (see Chapter 42 ):

• 1.
  

  Thiazides inhibit Na ⁺ /Cl ⁻ co-transporters in the proximal diluting segment of the distal collecting tubule and early collecting duct. The diuretic effect of the thiazides (except metolazone and indapamide) is less effective in patients with renal impairment. If used long term, thiazides inhibit maximal reabsorption of Na ⁺ to about 3% to 5% of the filtered load.

  
  
• 2.
  

  Loop diuretics have a short duration of action and hence are rarely used as first-line drugs for treatment of hypertension. They act on the medullary and cortical thick ascending limb segments of the nephron to prevent Na ⁺ , Cl ⁻ , and water reabsorption. There is some debate as to whether they also have other actions, such as systemic vasodilation and a reduction in left ventricular filling pressure secondary to preload reduction due to venodilation. However, they are useful if volume expansion contributes in part to the etiology of the hypertension (in patients with renal failure or from use of vasodilator drugs).

  
  
• 3.
  

  Of the potassium-sparing diuretics, both amiloride and triamterene have weak antihypertensive effects. However, spironolactone (an aldosterone antagonist) can be useful as an antihypertensive treatment in primary or secondary hyperaldosteronism or if the hypertension is treatment resistant. This class of diuretics has relatively weak natriuretic effects, with a maximal excretion of only about 1% to 2% of filtered Na ⁺ load.

Centrally Acting Agents

Most centrally acting antihypertensive drugs are no longer widely used. However, identifying their sites of action illustrates the diversity of approaches used to reduce blood pressure.

Reserpine acts to deplete neuronal stores of catecholamines both centrally and peripherally at the postganglionic neuron. Its mechanism of action is related to inhibition of norepinephrine and dopamine uptake into terminal synaptic vesicles, leading to increased breakdown of norepinephrine and reduced conversion of dopamine to norepinephrine. Although reserpine crosses the blood-brain barrier, this is probably not the site of its antihypertensive effect.

Bethanidine, guanethidine, and debrisoquin are selective postganglionic neuron blockers that act to inhibit release of norepinephrine from peripheral sympathetic nerve terminals. Although the exact mechanism of action of these drugs is not clear, there is evidence that the drugs must be actively taken up into neurons, where they accumulate in synaptic vesicles, causing norepinephrine depletion. Their antihypertensive effects are through reduced adrenergic synaptic transmission.

α ₂ Adrenoreceptor Agonists

α ₂ Receptor agonists have several distinct pharmacologic effects—sedation, analgesia, and hypotension. The α ₂ adrenoceptor is coupled to a Gi protein complex, which inhibits adenylyl cyclase and Ca ²⁺ and K ⁺ ion channels. The net result of α ₂ agonist binding is reduced cAMP production, hyperpolarization, and decreased intracellular Ca ²⁺ . α ₂ Receptors occur both presynaptically and postsynaptically. Stimulation of presynaptic α ₂ receptor decreases central sympathetic outflow. Agonist stimulation of postsynaptic α ₂ receptors mediates the sedative and analgesic effects.

Some of the earliest antihypertensive therapies were based on drugs acting on the control mechanisms in the central nervous system (CNS). There are α ₂ adrenoceptors in the locus coeruleus in the floor of the fourth ventricle, where α ₂ agonists act to cause sedation. The locus coeruleus also has afferent connections from the rostral ventrolateral medullary nuclei and efferent connections to noradrenergic fibers connecting to the thalamus and elsewhere. The α ₂ agonists also block salivary gland secretion. Effects in the nucleus tractus solitarius lead to inhibition of sympathetic activity and reduce peripheral vasoconstriction. These drugs are no longer widely used in the treatment of hypertension, with the exception of α-methyl DOPA for treatment of preeclampsia of pregnancy.

Excessive hypotension secondary to α ₂ agonist therapy can be reversed by vasopressors and inotropes. The use of ephedrine, phenylephrine, and dobutamine, but not norepinephrine, can be accompanied by an enhanced pressor response due to the β effects of these agents.

There are three main classes of α ₂ agonists: (1) the phenylethylates (α-methyl DOPA, guanabenz), (2) the imidazolines (clonidine, dexmedetomidine, mivazerol), and (3) the oxaloazepines.

α-Methyl DOPA is converted in noradrenergic neurons to the false transmitter α-methyl norepinephrine, which is a potent α ₂ agonist. It stimulates brainstem postsynaptic α ₂ receptors to decrease sympathetic tone and systemic vascular resistance.

Clonidine acts as a presynaptic α ₂ agonist on receptors in the brainstem, leading to reduction in sympathetic outflow and an increase in vagal activity. After intravenous dosing, there can be an initial transient hypertensive response due to peripheral vasoconstriction through α ₁ and α _2B interactions. In contrast to α ₂ agonists, such as α-methyl DOPA, imidazoline compounds produce hypotension following direct intramedullary injection. This led to the proposal of the presence of nonadrenergic receptors in the lateral reticular nuclei of the ventrolateral medulla (VLM). Two types of nonadrenergic imidazoline receptors have been identified: I ₁ receptors in the brain and I ₂ receptors in the brain, pancreas, and kidney. A number of the α ₂ agonists also have activity at I ₁ receptors. It is likely that they mediate their effects through a G protein–coupled mechanism that results in an increase in arachidonic acid and the subsequent release of prostaglandins. This led to the development of two specific I ₂ receptor agonists with more ideal hemodynamic profiles: monoxidine and rilmenidine. Both drugs have a weaker affinity for central α adrenoreceptors than α-methyl DOPA and clonidine. Other α ₂ agonists include dexmedetomidine, which has a greater selectivity and specificity for α ₂ receptors than clonidine (α ₂ : α ₁ 1620 : 1 compared with 200 : 1); and mivazerol (119 : 1; Fig. 26.4 ). This latter sympatholytic drug has been examined for a role in myocardial protection, but there are no published studies examining its use in the treatment of perioperative hypertension.

Mechanisms of action of α ₂ adrenoreceptor agonists and I ₁ imidazoline receptor agonists.

Monoxidine is a selective imidazoline receptor agonist that stimulates I ₁ receptors in the VLM, thereby decreasing sympathetic outflow and lowering blood pressure. In contrast to some other drugs, its use is not associated with a reflex tachycardia.

α ₁ Adrenoreceptor Antagonists

Agonists of the α ₁ adrenoreceptor leads to an increased intracellular Ca ²⁺ . The α ₁ agonist–receptor interaction leads to activation of phospholipase C (linked to Gq), which increases hydrolysis of phosphatidylinositol bisphosphate (PIP ₂ ) and increases synthesis of the second messengers DAG and 1,4,5-inositol trisphosphate (IP ₃ ). DAG activates protein kinase C while IP ₃ increases the intracellular Ca ²⁺ concentration by releasing Ca ²⁺ from the SR. There is also evidence that IP ₃ causes an increase in the Ca ²⁺ sensitivity of the contractile proteins. The phosphorylated product of IP ₃ (IP ₄ —1,3,4,5-inositol tetraphosphate) has been suggested as the messenger that enhances Ca ²⁺ flux across the cell membrane, causing vasoconstriction.

The α ₁ selective antagonists block α ₁ receptors to prevent Ca ²⁺ increases, thus leading to smooth muscle relaxation in arterioles and venous capacitance vessels.

There are two types of α ₁ antagonists:

• 1.
  

  Selective α ₁ antagonists: doxazosin, terazosin, prazosin, and indoramin

  
  
• 2.
  

  Nonselective α ₁ antagonists: phentolamine and phenoxybenzamine

While the selective antagonists act in a competitive manner, phenoxybenzamine combines irreversibly with the α ₁ receptors and so has a prolonged duration of effect. Phentolamine is a short-acting, reversible antagonist.

Nitrovasodilators

NO was identified as the “endothelium-dependent relaxing factor” by Furchgott and Zawadski in 1980 and its mechanism was defined by Palmer and colleagues. NO is an endogenous vasodilator that causes renal vasodilatation, leading to a diuresis and natriuresis and resulting in reduced blood pressure. There is some suggestion that deficiency in NO could contribute to the etiology of high blood pressure.

NO stimulates guanylyl cyclase to produce cyclic guanosine monophosphate (cGMP), which activates cGMP-dependent protein kinase (PKG). PKG then activates myosin light chain phosphatase (MLCP) to dephosphorylate myosin light chains and hence produce vascular relaxation. NO also activates sarcoplasmic and endoplasmic reticular Ca ²⁺ -ATPase to enhance reuptake of Ca ²⁺ , an effect that is cGMP independent. NO might also activate K ⁺ channels, resulting in membrane hyperpolarization, thus closing voltage-gated Ca ²⁺ channels ( Fig. 26.5 ).

Mechanism of action of nitric oxide and nitric oxide donors on vascular smooth muscle. cGMP, Cyclic guanosine monophosphate; GMP, guanine monophosphate; GTP, guanine triphosphate; NO, nitric oxide.

There are a number of NO donors. Some vasodilators release NO spontaneously (sodium nitroprusside) while others (organic nitrates such as nitroglycerin) need active reduction of the nitrate radical by intracellular sulfhydryl groups. All NO donors are potentiated by phosphodiesterase-5 inhibitors that reduce hydrolysis of cGMP (see later discussion).

Nitrites act as both arterial and venous dilators. They are usually associated with a reflex increase in heart rate; hence they are often coadministered with β blockers.

Sodium nitroprusside (SNP) is broken down in red cells with liberation of cyanide and NO. SNP has a rapid onset of action and is of short duration (1–2 minutes). While breaking down to form NO, SNP interacts with oxyhemoglobin to form cyan-methemoglobin and cyanide. The latter is converted to thiocyanate through transsulfation by the liver enzyme rhodanase, with thiosulfate acting as the sulphur donor. There are still issues over the total safe dose of SNP. Prolonged administration leads to accumulation of thiocyanate and cyanide, with the development of venous hyperoxemia and metabolic acidosis.

Nitrates undergo denitration to produce NO, their active component. Denitration can involve reaction with sulfhydryl groups or depends on the action of glutathione-S-transferase, cytochrome P450, and xanthine oxidoreductase. A stepwise increase in the dose of infused nitrate leads to a reduction in venous tone and central venous pressure. This is accompanied by a gradual decrease in systemic pressure. Administration of bolus doses of nitrates causes significant and immediate decreases in arterial pressure.

Glyceryl trinitrate (GTN), or nitroglycerin, acts as an NO donor, with a greater action on venous rather than arteriolar vessels. Its use can lead to tachyphylaxis due to a decrease in NO formation through generation of superoxide and peroxynitrite free radicals that inhibit aldehyde dehydrogenase. Without this enzyme, the conversion of organic nitrates and nitroglycerin to NO is impaired. In addition to decreasing blood pressure, nitroglycerin also reduces preload and myocardial oxygen demand. Nitroglycerin is a coronary vasodilator (including relaxation of stenosed vessels) and brings about an increased collateral coronary flow, improved subendocardial perfusion, and improved diastolic function. Because nitroglycerin undergoes extensive first-pass metabolism after oral dosing, nitrates are administered orally as isosorbide dinitrate (ISDN) and its metabolite isosorbide mononitrate (ISMN). Although the main use of nitroglycerin, ISDN, and ISMN is for antiangina therapy, they can also be used by titration for the control of blood pressure in the cardiac patient.

Adenosine stimulates purinergic receptors (P ₁ and P ₂ ) on endothelial cells to stimulate NO production. Adenosine also has direct effects on smooth muscle via a G protein–coupled pathway and activates ATP-sensitive K ⁺ channels, leading to membrane hyperpolarization and relaxation. Adenosine receptor blockers prevent Ca ²⁺ entry during phase 1 of the action potential, thus causing vascular relaxation. Although predominantly a coronary vasodilator, it can decrease blood pressure. It is not absorbed from the gut; thus, it is given by the intravenous route. The half-life after intravenous dosing is less than 10 seconds. It is intracellularly phosphorylated to AMP and then deaminated to inosine, hypoxanthine, xanthine, and uric acid. Both theophylline and other xanthines are antagonists at both P ₁ and P ₂ receptors; hence, their concurrent use increases dose requirements for adenosine. The uptake of adenosine into coronary endothelial cells is inhibited by dipyridamole.

Other Vasodilators

Minoxidil opens ATP-sensitive K ⁺ channels in vascular smooth muscle, hyperpolarizes the cell membrane, and closes voltage-gated Ca ²⁺ channels, leading to smooth muscle relaxation and vasodilation.

Hydralazine acts by promoting the influx of K ⁺ into vascular smooth muscle cells, thereby causing hyperpolarization and muscle relaxation. It can also cause arterial vasodilation by promoting smooth muscle relaxation through activation of guanylyl cyclase, leading to an increase in cGMP. Other mechanisms of action include inhibition of Ca ²⁺ release from the SR, reduction in Ca ²⁺ stores in the SR, and stimulation of NO formation by the vascular endothelium.

Diazoxide is chemically similar to thiazide diuretics but causes Na ⁺ retention. It is a powerful antihypertensive agent due to peripheral vasodilation secondary to opening K ⁺ channels.

Nicorandil promotes vasodilation of both systemic and coronary arteries by opening ATP-sensitive K ⁺ channels, hyperpolarization of the membrane, and reduced opening of voltage-gated Ca ²⁺ channels and therefore vascular smooth muscle relaxation. This is enhanced by the local production of NO from a nitrate-like action that also causes venodilation.

Ganglionic blockers formerly played a significant role in the modulation of blood pressure. Now, only trimethaphan is used (rarely) in hypertensive emergencies or for the production of controlled hypotension during surgery. Ganglionic blockers act by inhibiting autonomic activity at both sympathetic and parasympathetic ganglia. The decrease in sympathetic outflow causes vasodilation.

Magnesium affects vascular tone by diverse mechanisms; it acts as a Ca ²⁺ channel antagonist, stimulates production of vasodilator prostaglandins and NO, and alters the response of vascular endothelium to vasoactive agonists.

Endothelin receptor antagonists reduce blood pressure by blocking the actions of endothelins. Endothelins act on both ET _A and ET _B receptors. Endothelin 1 (ET-1) causes vasoconstriction through activation of both types of receptor on vascular smooth muscle cells. The receptors are coupled to Gq, with activation leading to increased synthesis and release of IP ₃ and Ca ²⁺ release from the SR. ET-1 synthesis and release is stimulated by a number of mediators: angiotensin II, arginine vasopressin, thrombin, cytokines, reactive oxygen species, and shear forces on the endothelium. Mixed ET receptor antagonists lower arterial blood pressure and prevent vascular and myocardial hypertrophy. Use of these drugs has also been studied in the treatment of pulmonary hypertension.

Peripheral dopamine (DA) agonists cause selective vasodilation of a number of vascular beds (splanchnic, cerebral, and coronary circulations) and can therefore be used in the treatment of hypertension. There are two subtypes of peripheral DA receptors. DA ₁ receptors are postsynaptic Gs protein–coupled receptors and cause vasodilation following increased intracellular cAMP and reduced intracellular calcium. DA ₂ receptors are presynaptic and coupled to Gi protein, leading to reduced cAMP, with membrane hyperpolarization and reduced norepinephrine release. The effects of dopamine on various catecholamine receptors are dose dependent: DA ₁ interactions occur at low doses, β ₁ at moderate doses, and α ₁ with high doses (see Chapter 25 ).

Fenoldopam is a selective DA ₁ receptor agonist without adrenergic receptor agonist properties. It is more potent than dopamine at DA ₁ receptors and is useful for control of blood pressure. It also has no agonist effects at the DA ₂ receptor. As such, it causes a decrease in blood pressure without increases in heart rate or contractility due to adrenergic effects. An advantage of the drug is that it does not cross the blood-brain barrier. It is available in the United States and some European countries, where it is recommended for acute or emergency control of blood pressure in the perioperative period.

Phosphodiesterases catalyze the hydrolysis of cyclic nucleotides. Phosphodiesterase inhibitors (PDEIs) block the hydrolysis of cAMP or cGMP, prolonging the effects on smooth muscle of signaling pathways involving these second messengers. An increase in cAMP (or cGMP) leads to phosphorylation of myosin light chain kinase, leading to a reduction of its activity due to reduced affinity for the Ca ²⁺ -calmodulin complex. The resulting reduced phosphorylation of myosin light chains leads to smooth muscle relaxation and vasodilatation. There are five subtypes of phosphodiesterase; PDE3 is inhibited by milrinone and enoximone, and PDE5 is inhibited by sildenafil and related compounds (see later discussion).

PDE3 inhibition prevents the breakdown of cAMP. Specific phosphodiesterases also hydrolyze cGMP, which might contribute to the vasodilator effect of PDE5 inhibitors. As a result of the inhibition of cyclic nucleotide breakdown, PDEIs cause a decrease in systemic vascular resistance and a small but significant fall in arterial pressure ( Fig. 26.6 ).

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