Why its needed?
What is advantage by prolonging drug action?
How to prolong?
Any clinical significance in prolonging action?
Advantages :-
Reduces frequency of adm -more convenient
Improves patient compliance-
single morning dose can’t be forgotten than a 6 or
8hly regimen (multiple dosing).
Quarterly administered contraceptive over one that
has take daily.
Avoids large Plasma fluctuations.
Maintains drug effect for the whole day/night.
e.g.. Antiasthmatics & anticonvulsants.
Drugs need not to be made long acting-
Drugs with brief therapeutic effect-hypnotics &
head ache remedy.
Drugs with long duration- doxycyclin, omeprazole,
digoxin & amlodipine.
Drugs with longer t1/2 > 12hr- no need of C.R.F.
C.R.F=controlled release formulation .
Methods to be used for prolongation of a drug:
By Retarding drug absorption.
By Retarding drug metabolism in the liver.
By Retarding drug excretion.
By using drugs of highly protein bound.
By modifying the molecular structure of a drug.
1. Retarding drug absorption.
a. Oral Route:-
Administration of drugs on full stomach.
Sustained Release Tablets & Spansules.
-Drugs particles are coated with resins, plastic materials or other
Substances - active ingredients released slowly into G.I.T.
Controlled Release Tab/Cap-
-semipermeable membrane control the release of active drug from
dosage form.
-prolongs actions by 4 to 8hrs & safely reaches the colon.
- drug release pattern & maintenance of plasma levels are different with
normal Tab/cap.
b)Parenteral Route–
1. By decreasing the vascularity of absorbing surface.
e.g. Adrenaline + lignocaine/procaine.
2.By decreasing the solubility of drug.
E.g. penicillin + procaine(poor H2O soluble solvent)&
Benzocaine
3.Administration of drug in oily solution/bees wax.
E.g. penicillin + aluminum monosterate (H2O repellant)
Pitressin tannate in oil.
4.Combining a drug with protein.
E.g. Protamine zinc insulin
5. Esterification:-(benzoate,enanthate,propionate)
Steroidal Sex Hormones are esterified with carboxylic acid
which are absorbed slowly.
6.Pegylation:
Combined with poly ethylene glycol
7.Depot Preparation:
e.g. Long acting Progesterone-contraceptive,
DOCA- Addison's disease.
c) Dermal Route:-
1.Pellet implantation -desoxycorticosterone acetate (DOCA)
2.Sialistic and biodegradable implants (Norplant)-oestrogens.
3.Transdermal System-
GTN ointment, Transdermal disc’s,
Patches(estradiol, scopolamine, corticosteroids)
d) Eye- Ocuserts e.g. pilocarpine for glaucoma
2) Retarding drug metabolism:
Hepatic Microsomal Enzyme system-biotransformation
Enzyme inhibitors- inhibits metabolism of certain drugs.
E.g.
1. Allopurinol inhibits the degradation of 6-MP.
2.Ritonavir boosts the levels of Indinavir.
3.Cilastatin protects Imipinem from degradation in
kidney by dehydropeptidase enzyme
4.L.dopa + carbidopa (dopa decarboxylase inhibitor)
3.Retarding renal excretion:-
Excretion of drugs by G.F can't be blocked/slowed.
Tubular secretion of drugs is an active process can be
blocked by competing substance/drugs.
E.g. Ampicillin
Penicillin, Probenecid(blocks OAT)
cephalosporin's, Tubular lumen
sulfa drugs urine
Mtx & Indomethacin penicillin
OAT
Probenecid
4) By increasing protein binding in plasma-
Drug congeners are prepared with high plasma protein
binding from which active drug is slowly released.
Long acting sulfonamide- sulfamethoxypyridazine
,sulfodoxin
-highly bound to plasma proteins.
Short acting sulfonamide- sulfadiazine.
-less bound to plasma proteins.
Suramin used to RX Trypanosomiasis-
-highly bound to plasma proteins.
Ptn bounded drug acts as a-
Drug acceptors
Drug reservoir
Pharmacologically inactive
Prolongs drug duration
Drug remains in vascular compartment(can’t diffuse thru’ membranes)
aVd is low(<5L)
Delays drug metabolism
Delays drug excretion
Decreases drug clearance & can’t be removed by hemodialysis.
Diminishes drug penetration into CNS.
Responsible for drug displacement interactions(toxicity)
Attains less conc. In ISF, CSF, tissues-therapeutic activity is low.
E.g- long acting sulfonamides used to Rx diseases
5) Drugs sequestered in adipose tissue-
e.g. Quinestrol - cyclopentyl ester of estradiol have prolonged
drug action.
6) By modifying the molecular structure of a drug-(SAR)
e.g.
Procaine is L.A- on I.V route adm-
- reduces cardiac rate & excitability
- but rapidly hydrolyzed
- hence cardiac action is too transient.
Procainamide - structurally similar to Procaine
- Resistance to hydrolysis,
- Longer acting RX cardiac arrhythmias.
SAR-Structure activity relationship.
PROCESSES METHODS EXAMPLES
Absorption Sustained, Spansules, Deriphylline,Iron,
Oral controlled released
formulations
Parenteral 1.Reducing solubility -procaine + penicillin
2.Altering particle size -Insulin zinc suspension(crystalline)
3.Pellet implantation -DOCA
4.Sialistic capsules -Testosterone
5. Reducing vascularity -Adrenaline+Lignocaine
6.Combining with Ptn -Protamine+Znic+Insulin
7.Esterification -Estrogens
Dermal TDS Scopolamine, clonidine, GTN,
pilocarpine
Distribution More Protein binding Sulphonamides-
drug sulfadoxine
Metabolism Cholinesterase inhibitors -physostigmine+Ach
peptidase inhibitors
-Cilastin prolongs action of
Imipenem
Excretion Competition for same -Probenecid prolongs action
transporters for T.Secretion of penicillin/ampicillin.
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