Prolongation of Drug Action

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Chapter: Essential pharmacology : Pharmacokinetics; Metabolism Excretion Of Drugs, Kinetics Of Elimination

It is sometimes advantageous to modify a drug in such a way that it acts for a longer period. By doing so:



It is sometimes advantageous to modify a drug in such a way that it acts for a longer period. By doing so:


§  Frequency of administration is reduced— more convenient.


§  Improved patient compliance—a single morning dose is less likely to be forgotten/omitted than a 6 or 8 hourly regimen; a monthly or quarterly administered contraceptive over one that has to be taken daily.


§  Large fluctuations in plasma concentration are avoided—side effects related to high peak plasma level just after a dose (e.g. nifedipine) would be minimized; better roundtheclock control of blood sugar, etc.


§  Drug effect could be maintained overnight without disturbing sleep, e.g. antiasthmatics, anticonvulsants, etc.


However, all drugs do not need to be made long acting, e.g. those used for brief therapeutic effect (sleepinducing hypnotic, headache remedy) or those with inherently long duration of action (doxycycline, omeprazole, digoxin, amlodipine). Drugs with t½ < 4 hr are suitable for controlled release formulations, while there is no need of such formulations for drugs with t½ >12 hr. Methods utilized for prolonging drug action are summarised below. Some of these have already been described.


1)  By Prolonging Absorption From Site Of Administration


a)    Oral


Sustained release tablets, spansule capsules, etc.; drug particles are coated with resins, plastic materials or other substances which temporally disperse release of the active ingredient in the g.i.t. Another technique (controlled release tablet/capsule; Fig. 3.7) utilizes a semipermeable membrane to control the release of drug from the dosage form. Such preparations prolong the action by 4 to 8 hours and no more, because in that time drug particles reach the colon. Also, the drug release pattern and consequently the attained blood levels of the drug may be more variable than the regular tablet of the same drug.


b) Parenteral


The s.c. and i.m. injection of drug in insoluble form (benzathine penicillin, lente insulin) or as oily solution (depot progestins); pellet implantation, sialistic and biodegradable implants can provide for its absorption over a couple of days to several months or even years. Inclusion of a vasoconstrictor with the drug also delays absorption (adrenaline with local anaesthetics).



(c) Transdermal drug delivery systems


The drug impregnated in adhesive patches, strips or as ointment applied on skin is becoming popular, e.g. GTN.


 2) By Increasing Plasma Protein Binding


Drug congeners have been prepared which are highly bound to plasma protein and are slowly released in the free active form, e.g. sulfadoxine.


 3) By Retarding Rate Of Metabolism


Small chemical modification can markedly affect the rate of metabolism without affecting the biological action, e.g. addition of ethinyl group to estradiol makes it longer acting and suitable for use as oral contraceptive. Inhibition of specific enzyme by one drug can prolong the action of another drug, e.g. allopurinol inhibits the degradation of 6mercaptopurine, ritonavir boosts the levels of indinavir, cilastatin protects imipenem from degradation in kidney.


4. By Retarding Renal Excretion


The tubular secretion of drug being an active process, can be suppressed by a competing substance, e.g. probenecid prolongs duration of action of penicillin and ampicillin.


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