Clinical Pharmacology of the Angiotensin Receptor Antagonists

OVERVIEW

Selective blockade of the angiotensin (AT₁) receptor is a novel means by which the renin‐angiotensin axis can be interrupted. Several compounds capable of blocking the AT₁ receptor are now marketed in the United States. Each of these compounds has a unique set of pharmacologic characteristics that ultimately influence the manner in which blood pressure is reduced. Often, the pharmacologic characteristics of an AT₁ receptor antagonist have been emphasized to support a superiority argument. Unfortunately, it has proven difficult to equate a specific pharmacologic feature—beyond that of duration of receptor binding—with a particular pattern of blood pressure reduction. Most angiotensin receptor antagonists are indicated for once‐daily dosing but may occasionally lose efficacy at the end of the dosing interval, thereby necessitating twice‐daily dosing. The issue of frequency of dosing is complex, in that sensitivity to a medication may dictate the need for multiple daily dosing to the same extent as a drug that has a shorter plasma or tissue half‐life.

Selective angiotensin receptor antagonists (AT₁‐Ras) are a relatively new class of drugs employed in the treatment of hypertension. These agents work selectively at the AT₁ receptor subtype, the receptor that mediates all of the known physiologic effects of angiotensin‐II that are relevant to cardiovascular and cardiorenal homeostasis. ¹ Each AT₁‐RA has a unique pharmacologic profile. ² , ³ The pharmacologic differentiation of the various compound AT₁‐Ras is a topic of growing relevance, in that individual drugs in this drug class may differ in their ability to reduce blood pressure (BP) ⁴ , ⁵ Since the release of the first AT₁‐RA, losartan (Cozaar®), in 1995, five other compounds have been developed and are now marketed in the U.S. These compounds are candesartan (Atacand®), eprosartan (Tevetan®), irbesartan (Avapro®), telmisartan (Mycardis®), and valsartan (Diovan®). In addition, three different fixed‐dose combination products are currently available: losartan/hydrochlorothiazide 50/12.5 and 100/25 mg (Hyzaar®); irbesartan/hydrochlorothiazide 150/12.5 and 300/12.5 mg (Avalide®); and valsartan/hydrochlorothiazide 80/12.5 and 160/12.5 mg (Diovan‐HCTZ®). Other fixed‐dose combination products with the AT₁‐Ras candesartan and telmisartan plus hydrochlorothiazide will soon be released. Currently available information does not suggest that any specific pharmacologic differences exist for these agents if they are administered alone or together with hydrochlorothiazide in a fixed‐dose combination product.

RECEPTOR OCCUPANCY

Receptor affinity is just one of several factors that influence the action of an AT₁‐RA. An AT₁‐RA is recognized as demonstrating insurmountable or noncompetitive blockade if increasingly higher concentrations of angiotensin‐II are unable to overcome receptor blockade. The terms surmountable, competitive, insurmountable, and noncompetitive are often used in an inconsistent fashion. ⁶ , ⁷ Eprosartan functions as a competitive antagonist; agonists and antagonists individually compete for receptor binding. Surmountable antagonism implies that antagonist blockade can eventually be overcome if high enough angiotensin‐II concentrations are present in the system being studied. Losartan demonstrates surmountable antagonism. Noncompetitive, irreversible antagonism involves the loss of receptor numbers by a process of chemical modification. Insurmountable antagonists are bound to their receptors in a semi‐irreversible fashion. An insurmountable antagonist releases from its receptor slowly. Valsartan, candesartan, irbesartan, telmisartan, and the active metabolite of losartan (E‐3174) demonstrate this form of antagonism. ⁸ , ⁹ , ¹⁰ To date, the specific mode of receptor occupancy has not been clearly linked with the blood pressure response to an AT₁‐RA.

BIOAVAILABILITY

The bioavailability of the individual AT₁‐Ras is quite variable (Table I). ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ Two of the AT₁‐Ras—losartan and candesartan cilexitil—are administered in a prodrug form, although technically speaking, losartan is an active compound, albeit one ultimately converted to a more potent E‐3174 metabolite. The bioavailability of eprosartan is low (≊13%), a phenomenon that is not due to high first‐pass elimination. ¹⁴ Irbesartan demonstrates a bioavailability profile with an absorption range between 60% and 80% and has no food effect. ¹⁷ , ¹⁸ Losartan has a moderate bioavailability (≊33%), with 14% of an administered dose transformed to the E‐3174 metabolite. ¹⁹ , ²⁰ Telmisartan appears to have a saturable first‐pass effect for its absorption; thus, the higher the dose the greater the absolute bioavailability. Unfortunately, the most pertinent absorption characteristic of individual AT₁‐Ras, which is day‐to‐day variability in bioavailability, is not routinely reported.

Table I.

BIOAVAILABILITY OF THE ANGIOTENSIN‐RECEPTOR ANTAGONISTS

Drug	Bioavailability (%)	Food Effect
Candesartan cilexitil 11 , 12	15	No
Eprosartan 13 , 14 , 15 , 16	6–29	AUC↓≊25%
Irbesartan 17 , 18	60–80	No
Losartan 19 , 20	33	AUC↓≊10%
Telmisartan 21 , 22	42–58	AUC↓6–24%
Valsartan 23 , 24	25	AUC↓≊50%
AUC=area under the curve: the amount of drug available over time.

VOLUME OF DISTRIBUTION/PROTEIN BINDING

The AT₁‐Ras typically have a volume of distribution (V_D) that approximates extracellular fluid volume, partly in relation to the extensive protein binding of these compounds. To date, the clinical significance of lower or higher VD of the AT₁‐Ras remains unclear. The VD of the AT₁‐Ras in disease states, such as renal failure, is unreported. Parenthetically, it has been suggested, though, that the greater the VD for an AT₁‐RA, the more likely it is that extravascular AT₁ receptors can be accessed. The protein binding of the AT₁‐Ras is typically well in excess of 90%. ²² , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ The exception to this pharmacologic characteristic is the AT₁‐RA irbesartan, which has the highest plasma free fraction (4%–5%). The extent of protein binding for the AT₁‐Ras remains fairly constant over a wide concentration range. The significance of the degree of protein binding remains to be determined.

METABOLISM AND ACTIVE METABOLITES

Metabolic conversion of an AT₁‐RA can be viewed in two different ways. First, it may be a step required in order to produce an active metabolite, such as is the case with losartan and candesartan cilexitil. Alternatively, metabolic conversion may simply be a factor in the disposition of a compound, with the metabolites being physiologically inactive. This is the case with irbesartan. Losartan, an active substrate molecule, is converted to its more active metabolite, E‐3174, ³¹ , ³² , ³³ whereas candesartan cilexitil, a prodrug, is hydrolyzed to the active compound candesartan in the course of absorption from the gastrointestinal tract. ³⁴

The metabolic conversion of candesartan cilexitil seems not to be influenced to any degree by disease states, genetic variation in metabolism, or chronic dosing. ³⁴ Questions have been raised, however, concerning the metabolic profile of losartan. In rare cases, certain enzyme variants may serve to decrease conversion of this agent to its active metabolite. To date, fewer than 1% of the population of patients exposed to therapy with losartan have this abnormal genetic profile for the metabolism of losartan. Thus, it is unlikely that a metabolic polymorphism for losartan breakdown will ever be found in a clinically important number of patients.

ROUTE OF ELIMINATION

It is well recognized that the systemic clearance of a compound is dependent on the integrity of both renal and hepatic function. If renal and/or hepatic dysfunction exists in a patient, repeated dosing with an antihypertensive compound will inevitably lead to drug accumulation and the need to adjust the dose in order to lessen concentration‐related side effects. The process of drug accumulation of an antihypertensive compound is most evident when angiotensin‐converting enzyme (ACE) inhibitors, which are mainly eliminated by the kidney, are chronically given to patients with renal insufficiency. ³ In these patients, significant drug accumulation occurs with repeated dosing, except in the case of the ACE inhibitors fosinopril and trandolapril. Both of these compounds undergo at least 50% hepatic clearance, which limits their systemic accumulation in the renal failure patient. ³⁵

The AT₁‐Ras have only recently been studied in terms of their renal and/or hepatic handling (Table II). Most of these drugs undergo a significant degree of hepatic elimination, with the exception of candesartan and the metabolite of losartan, which are 40% and 50% hepatically cleared, respectively. ³⁶ , ³⁷ Irbesartan and telmisartan undergo the greatest degree of hepatic elimination among the AT₁‐Ras, with <5% of their systemic clearance via the kidneys. ²¹ , ³⁸ Valsartan and eprosartan both undergo about 30% renal clearance. ³⁹ , ⁴⁰ , ⁴¹ On the surface, the mode of elimination for an AT₁‐RA may seem a trivial issue. In reality, it proves to be an important variable in the renally compromised patient and may, in fact, dictate some change in therapy. In those who develop acute renal failure when given a renally cleared ACE inhibitor or AT₁‐RA, the duration of any renal failure episode is linked to the kidney's inability to eliminate the compound. ⁴² Although this has not been formally studied, compounds that are extensively hepatically cleared should cause fewer renal problems.

Table II.

ROUTES OF ELIMINATION OF AT₁‐Ras (EXPRESSED AS PERCENTAGES)

Drug	Renal	Hepatic
Candesartan 36	60	40
Eprosartan 40 , 41	30	70
Irbesartan 38	1	99
Losartan 37	10	90
E‐3174 37	50	50
Telmisartan 21	1	99
Valsartan 36	30	70

To date, very few studies have been conducted assessing the BP‐lowering effect of AT₁‐Ras in patients with decreased renal function. ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶ In studies so far completed, the BP‐lowering effect of these compounds is clearly maintained in the renal failure patient and, in certain instances, may be significant. Additional experience is needed with the AT₁‐Ras before definitive statements can be made concerning their efficacy in this population, and whether relevant drug accumulation occurs with the AT₁‐Ras that undergo at least 50% renal clearance, as is the case with the E‐3174 metabolite of losartan and candesartan.

RECEPTOR BINDING AND HALF‐LIFE

The half‐life of a compound is a pure pharmacokinetic term, and does not always correlate exactly with the duration of effect of a compound. This has typically been the case with antihypertensive compounds, including both ACE inhibitors and the AT₁‐Ras. The discrepancy between the pharmacokinetic and pharmacodynamic half‐life of a compound derives from the fact that the predominant site of drug action is in locations other than the plasma compartment. Because of the inability to sample at these extravascular sites of action of many drugs, the more meaningful tissue‐based half‐life cannot be determined. This is particularly the case for the AT₁‐Ras, since AT₁ receptors are to be found in multiple locations outside the vascular compartment, and blocking AT₁ receptors at these alternative locations may, in an as yet undefined way, influence the manner in which BP is reduced.

Despite this reservation, the pharmacokinetic half‐life of an AT₁‐RA roughly approximates its duration of effect. Several of the AT₁‐Ras, such as candesartan, telmisartan, and irbesartan, are once‐daily compounds in pharmacokinetic terms. For example, irbesartan has a half‐life of 11–15 hours and, like candesartan and telmisartan, clearly behaves as a once‐daily compound. ⁴⁷ The true impact of pharmacologic half‐life for these compounds is probably in relation to the fact that drug remains available in suitable amounts for a longer period of time as new AT₁ receptors are formed. This phenomenon becomes obvious if the pressor response to angiotensin‐II is evaluated.

CONCLUSIONS

The pharmacokinetics of a compound can influence its onset and duration of effect and, in certain instances, its side‐effect profile. Furthermore, a compound's dose‐response relationship can be closely associated with its unique pharmacokinetic profile. These concepts are of particular relevance to antihypertensive drugs. The primary pharmacokinetic parameters, which influence the selection of an antihypertensive agent, include absorption/bioavailability, volume of distribution, compound half‐life (plasma and tissue‐based components), and mode of elimination (hepatic and/or renal).

As previously noted, the absorption rate of a compound generally determines its onset of action. For example, buccally administered nifedipine is rapid‐acting because of its quick absorption. Another example of absorption rate dictating onset of response is captopril. Among the ACE inhibitors, it is the most rapidly absorbed and consequently effects blood pressure change the most quickly. The extent of compound absorption is an additional key determinant of drug effect. Complete or relatively complete absorption is a useful compound feature—in part because anticipated day‐to‐day variation in drug absorption influences the body's total amount of drug exposure. Absorptive variability is of most relevance when lowend therapeutic doses are given.

The V_D of a compound is a relative consideration in how an antihypertensive compound reduces blood pressure. Compounds with a more extensive V_D are—at least in theory—characterized by greater penetration into deep tissue compartments, from which other compounds (with a small V_D) might be excluded. Finally, the half‐life of a compound approximates, in a relatively crude fashion, the duration of its effect. For many antihypertensive compounds, the half‐life at the main site of action would more reliably predict duration of effect if such were measurable. Unfortunately, the inability to sample at such locations limits the understanding of the concentration‐effect relationship for most drugs. An example of this is the compound clonidine, whose primary locus of action is within the central nervous system. Finally, in the instance of the AT₁‐Ras, the issue of receptor affinity must be considered if AT₁‐Ras are to be compared. In that respect, certain of the AT₁‐Ras, such as irbesartan, candesartan, and telmisartan, are quite proficient.