Sequential blockade

Single agents are seldom used to treat HIV infection. Instead, multidrug therapy is used to counteract the rapid mutation rate of HIV and to minimize drug toxicity. Highly active antiretroviral therapy (HAART) uses combinations of reverse transcriptase inhibitors and protease inhibitors (Table 51.1). In this system, drugs working by different mechanisms produce a sequential blockade of steps required for viral reproduction. It is... 

The combined use of sulfonamides or sulfones with dihydrofolate reductase inhibitors, such as trimethoprim Bactrim, Septra) or pyrimethamine Fansidar), s, a good example of the synergistic possibilities that exist in multiple-drug chemotherapy. This type of impairment of the parasite s metabolism is termed sequential blockade. Using drugs that inhibit at two different points in the same biochemical pathway produces parasite lethality at lower drug concentrations than are possible when either drug is used alone. 

A widely available fixed combination is co-trimoxazole (Bactrim, Eusaprim, Septrin), which contains trimethoprim and sulfamethoxazole in a ratio of 1 5. Both trimethoprim and sulfamethoxazole have favorable and comparable pharmacokinetics and the combination is bactericidal (4). Synergy between trimethoprim and sulfonamides has conventionally been ascribed to sequential inhibition of dihydropteroate synthetase by sulfonamides (in competition with pora-aminobenzoic acid) and of dihydrofolate reductase by trimethoprim (in competition with dihydrofolate). However, sulfonamides in high concentrations also inhibit dihydrofolate reductase. Thus, an initial partial sequential blockade by trimethoprim (inhibition of dihydrofolate reductase) and sulfonamides (inhibition of dihydropteroate synthetase) leads to defective protein synthesis and cytoplasmic damage, which in turn results in marked increases in the uptake of both agents and double strength inhibition of dihydrofolate reductase (5). 

Co-trimoxazole is a mixture of sulphamethoxazole (five parts) and trimethoprim (one part). The reason for using this combination is based upon the in vitro finding that there is a sequential blockade of folic acid synthesis, in which the sulphonamide is a competitive inhibitor of dihydropteroate synthetase and trimethoprim inhibits DHFR (see Chapter 12). The optimum ratio of the two components may not... 

Gll. Gots, J. S., and Gollub, E. G., Sequential blockade in adenine biosymthesis by genetic loss of an apparent bifunctional deacylase. Proc. Natl. Acad. SH. U.S. 43, 826-834 (1957). 

Another concept that should be considered at this point is sequential blockade as it relates to chemotherapy. Considering the outline of the folate biosynthesis scheme (Fig. 7-8), the likelihood that the blockade with selective agents of more than one reaction in sequence will increase the therapeutic value of treatment is apparent. 

Even though the synergism observed with antifolate-sulfonamide combinations appears real, whether or not the mechanism is truly a sequential blockade is questionable. For example, it was shown that a potent DHFR inhibitor, 2,4-diaminopteroyl aspartate, is not synergistic with sulfamethoxazole. In addition, it was found that DHFR isolated from E. coli could be inhibited by sulfonamides, suggesting a multiple simultaneous inhibition of DHFR by both drugs. Curiously, it was also found that the TM potentiates sulfonamides that alone are resistant to the bacterium tested. 

Thioguanine has multiple metabolic effects. Its tumor inhibitory properties may be due to one or more of its effects on feedback inhibition of de novo purine synthesis inhibition of purine nucleotide interconversions or incorporation into DNA and RNA. The net conseqnence of its actions is a sequential blockade of the synthesis and utilization of the purine nucleotides. 

Sequential blockade The combined action of two drugs that inhibit sequential steps in a pathway of bacterial metabolism... 

Figure 46-1. Inhibitory effects of sulfonamides and trimethoprim on folic acid synthesis. Inhibition of two successive steps in the formation of tetrahydrofolic acid constitutes sequential blockade and results in antibacterial synergy. (Modified and reproduced, with permission, from Katzung BG [editor] Basic Clinical Pharmacology, 8th ed. McGraw-Hill, 2001.)...

Trimethoprim plus sulfamethoxazole When the two drugs are used in combination, antimicrobial synergy results from the sequential blockade of folate synthesis (Figure 46-1). The drug combination is bactericidal against susceptible organisms. 

A) This combination is effective in the treatment of pneumonia due to Pneumocystis carinii The dmgs produce a sequential blockade of folic acid synthesis Fever and pancytopenia occur frequently when these drugs are used in AIDS patients The combination is appropriate for the treatment of streptococcal pharyngitis The combination is effective in the management of acute exacerbations of chronic bronchitis... 

The persistent suppression of bacterial growth that may occur following limited exposure to some antimicrobial dmgs is called (A) Time-dependent killing The postantibiotic effect Clinical synergy Concentration-dependent killing Sequential blockade... 

Sequential blockade Actions of two or more drugs that interfere with sequential steps in a metabolic pathway... 

Dihydropteroate synthase Sporozoans (eg, plasmodium, toxoplasma, and eimeria species) lack the ability to utilize exogenous folate and therefore possess enzymes for its synthesis these enzymes can be inhibited by drugs. Sulfonamides, which are antimetabolites of PABA, inhibit dihydropteroate synthase. Sequential blockade ctin be achieved with a sulfonamide and an inhibitor of dihydrofolate reductase (eg, pyrimethamine) such drug combinations are effective in malaria and toxoplasmosis. 

Pyrimethamine is synergistic with sulfadoxine against malarial parasites (sequential blockade)... 

Antiprotozoal antifol inhibiting DHF reductase and synergistic, via sequential blockade, with sulfadiazine against Toxoplasma gondii. Folinic acid is needed to offset hematologic toxicity. 

Bactericidal actions occur through sequential blockade of folic acid synthesis Folinic acid will reduce hematologic side effects... 

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