Altizide INN, Althiazide USAN,
K. Altizide INN, Althiazide USAN,
3-[(Allythio) methyl]-6-chloro 3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulphonamide 1, 1- dioxide ; Althiazide (R) (Pfizer).
2.2.1.1. Mechanism of Action
The mechanism of action of the thiazide diuretics shall now be discussed individually in the pages that follows :
2.2.1.2. Chlorothiazide
The epoch making era of wonderful ‘drug discovery’ of benzothiadiazines commenced with the synthesis (1957) and the remarkable valuable diuretic characteristic features of this ‘drug’ i.e., chlorothiazide (CTZ). It acts by depliting Na and followed by reduction in the plasma volume. Besides, it also reduces in the peripheral resistance. Refractoriness of the ‘drug’ is comparatively uncommon, even after a prolonged span of continuous usage.
2.2.1.3. Hydrochlorothiazide (HCTZ)
Slightly more soluble in water than chlorothiazide, but its mode of action is practically the same as that of chlorothiazide.
2.2.1.4. Hydroflumethiazide
The replacement of the Cl-atom at C-6 with trifluoromethyl function (CF 3 ) renders the ‘drug’ more potent in its therapeutic activity.
2.2.1.5. Bendroflumethiazide
Additional benzyl moiety at C-3 of hydroflumethiazide attributes far better potency than the parent drug in terms of its diuretic profile.
2.2.1.6. Benzthiazide
Additional benzyl thiomethyl group at C-3 of chlorothiazide renders the drug more broad-spectrum in its therapeutic values i.e., it serves both as a diuretic and also as an antihypertensive agent.
2.2.1.7. Cyclothiazide
The only glaring difference between this ‘drug’ and chlorothiazide is the presence of 5-norboren- 2-yl lipid-soluble moieties strategically located at the C-3 position which renders the drug both orally effective as a diuretic and antihypertensive i.e., the two pharmacological characteristics desirably present in the same drug molecule.
2.2.1.8. Cyclopenthiazide
The ‘drug’ exhibits its activitiy quite similar to those of HCTZ. However, in suceptible patients potassium supplements or a potassium-sparing diuretic may be absolutely important and necessary.
2.2.1.9. Methyclothiazide
The dosage regimen of clinically used compounds invariably ranges between 1 to 2000 mg. Besides, there exists one more important and clinically useful variable within which a choice is obviously preferable is the duration of action. Methyclothiazide possesses a range of 24+ hours in comparison to CTZ having as much a low range of 6 hours.
The ‘drug’ is an orally effective as well as long-acting thiazide diuretic and antihypertensive. It resembles CTZ with respect to its pharmacologic actions, therapeutic uses and untoward effects.
2.2.1.11. Polythiazide
It is also a long-acting diuretic and antihypertensive agent that causes diuresis within 2 hr, attains a peak in 6 hr and lasts 24 to 48 hr. The mean plasma half-lives for absorption and elimination are 1.2 and 25.7 hour respectively. It has been observed that nearly 20% of the drug gets excreted unchanged in the urine. On being compared on a milligram basis, 2 mg of polythiazide has almost nearly the same diuretic activity as produced by 500 mg of CTZ.
2.2.1.12. Altizide (Althiazide)
It is a thiazide diuretic having action very similar to hydrochlorothiazide (HCTZ). It is in- variably administered in combination with spironolactone.
2.2.1.13. SARs of Thiazide Diuretics
The SARs of these benzene disulphonamide structural analogues yielded a broad-spectrum of compounds having a relatively high degree of diuretic activity, which are summarized as stated under :
(1) Thiazide diuretics are found to be weakly acidic in nature having a benzothiadiazine 1, 1-dioxide nucleus.
C HAPTER
(2) Chlorothiazide (CTZ) being the simplest member of this series of structural analogues having two pKa (dissociation constant) values of 6.7 and 9.5. The two acidic zones in CTZ are virtually due to the
presence of : (a) presence of a H-atom at the 2-N that essentially attributes the most acidic character by virtue of the influence of the prevailing electron withdrawing effects of the neighbouring
sulphone moiety ; and (b) presence of the sulphonamide (–SO 2 NH 2 ) functional moiety strategically located at C-7 position which affords an additional environment (zone) of creating acidity in the molecule ; however, its acidic influence is much less than the 2-N proton. Importantly, these acidic protons enable the formation of the corresponding wa- ter-soluble sodium salt which may be gainfully used for IV-administration of the diuretics as shown below :
(3) Presence of an electron-withdrawing moiety at C-6 is an absoluble necessity for the diuretic activity. A few important and vital observations are as enumerated below : (a) Practically negligible diuretic activity is obtained by having a H-atom at C-6 ;
(b) Substitution with a chloro or trifluoromethyl moiety at C-6 are quite active pharmacologically. (c) Further, the CF 3 moiety renders the resulting diuretic compound more lipid-soluble and also with a much longer duration of action in comparison to its chloro-substituted derivatives ;
MEDICINAL CHEMISTRY
(d) Presence of electron-releasing moieties, namely : methyl or methoxyl at C-6 position attributes significantly reduced diuretic activity.
(4) Removal or possible replacement of the sulphonamide function at C-7 results into such compounds possessing either little or almost no diuretic activity.
(5) Saturation of the prevailing double-bond between 3 and 4 positions to give rise to a corresponding 3, 4-dihydro structural analogue which is observed to be having nearly 10 times more diuretic activity than the unsaturated analogue.
(6) Introduction of a lipophilic functional moiety at C-3 position renders a marked and pronounced enhancement in the diuretic potency. For instance : aralkyl, haloalkyl, or thioether substitution, enhances the lipoidal solubility of the molecule to a considerable extent thereby producing compounds with a much longer duration of action.
(7) Alkyl substitution on the N-2 position is observed to lower the polarity and ultimately enhancing the duration of the ensuing diuretic action.