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