Pro Drug: Basic concepts and Applications
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Prodrugs are biologically inert derivatives of drug molecules that convert in vivo to release pharmacologically active products, offering advantages such as reduced side effects and targeted delivery. The document outlines their historical development, objectives in drug formulation, classifications such as carrier-linked and bioprecursor prodrugs, and various applications aimed at improving pharmacokinetics and therapeutic efficacy. Prodrug design plays a crucial role in enhancing drug absorption, stability, and efficacy while minimizing toxicity.
Pro Drug: Basic concepts and Applications
- 1. PRODRUGS: BASIC CONCEPTS AND APPLICATIONS OF PRODRUGS SUBMITTED TO: Dr. Ajmer Singh SUBMITTED BY: Prabhjot Kaur 1736
- 2. INTRODUCTION A Pro Drug can be defined as a biologically inert derivatives of drug molecules that undergo an enzymatic and/or chemical conversion in vivo(inside body)to release the pharmacologically active product. A prodrug is a chemically modified inert drug precursor ,which upon biotransformation liberates the pharmacologically active compound.
- 3. Advantages and Disadvantages : ADVANTAGES: 1.It reduces adverse effects of drugs. 2.Drug can be targeted to the desired sites. 3.Synergistic effect can be obtained without side effects. 4.Gives additional biological action as that of parent drug. DISADVANTAGES: 1.Formation of toxic metabolities. 2.The active doses of two mutual prodrugs of same parent drugs may appear to be same in preclinical studies but may be quite different in clinical investigations. 3.During its activation stage,a prodrug might consume a vital cell constituent(eg.glutathion) leading to its its depletion.
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- 5. History Of Prodrugs: The term prodrug was introduced in 1958 by Adrien Albert. For the first time,concept was intensionally used by the Perk- Devis company for modification of chloramphenicol structure . It was done in order to improve its bitter taste and poor solubility in water. The first compound(acetanalide)fulfilling the criteria of prodrugs was introduced was introduced by Cahn and Hepp in 1867. ACETANALIDE ACETAMINIPHEN (prodrug) (anti-pyretic drug) Another historical prodrug is Aspirin , synthesized in 1897 by Felix Hoffman and introduced into medicine by Dreser in 1899.
- 6. OBJECTIVES OF PRODRUGS 3 basic objectives in prodrug research are : 1) Pharmaceutical objectives 2) Pharmacokinetic objectives 3) Pharmacodynamic objective
- 7. OBJECTIVES continues… 1.Pharmaceutical objectives: o To improve solubility,chemical stability and organoleptic properties . o To decrease irritation and/or pain after local administeration. 2.Pharmacokinetics objectives: o To improve absoption o To decrease pre systemic metabolism to improve time profile. 3.Pharmacodynamic objectives: o To decrease toxicity and improve therapeutic dose. o To design single chemical entites combining two drugs.
- 8. CLASSIFICATION OF PRODRUGS Classification of prodrugs can be done in two ways: 1.On the basis of structural association 2.Novel Classification of molecules a)Carrier linked prodrugs a) Type I Prodrugs .)Bipartite Prodrugs b) Type II Prodrugs .)Tripartite Produgs .)Mutual Prodrugs b)Bioprecursor Prodrugs
- 9. a)CARRIER LINKED PRODRUGS: Active drug is covalently linked to an inert carrier or transporter moiety. They have enhanced lipophilicity due to attached carrier. The active drug is released by hydrolytic cleavage, either chemically or enzymatically 1)On the basis of structural assosciation:
- 10. . 1)Bipartite Prodrug: • It is composed of one carrier (group) attached to the drugs directly. • Such prodrugs have greatly modified lipophilicity due to the attached carrier. The active drug is released by hydrolytic cleavage either chemically or enzymatically. • E.g. Tolmetin-glycine prodrug (NSAID).
- 11. . 2)Tripartite Prodrug: • Drug is linked to Structure Carrier indirectly. • The carrier group is attached via linker to drug. • Eg:
- 12. . 3) Mutual Prodrugs: • A mutual prodrug consists of two pharmacologically active agents coupled together so that each acts as a promoiety for the other agent and vice versa. • A mutual prodrug is a bipartite or tripartite prodrug in which the carrier is a synergistic drug with the drug to which it is linked • Eg: hydrolysis + • acetyl salicyllic acid paracetamol Benorylate
- 13. . 2)BIOPRESSOR PRODRUGS: Bio- precursor prodrugs produce their effects after in vivo chemical modification of their inactive form. Bioprecursor prodrugs rely on oxidative or reductive activation reactions. These prodrugs are metabolized into a new compound that either may itself be active metabolite or further metabolized to an active metabolite.
- 14. Biopressor prodrugs continues… Eg: phenylbutazone. Phenylbutazone gets metabolized to oxyphenbutazone that is responsible for the anti inflammatory activity of the parent drug. DRUG PRODRUG Oxyphenbutazone phenybutazone
- 15. 2)Novel Classification: According to novel classification prodrugs are classified into two subtypes.These are as follows: ➢ Type I Prodrugs ➢ Type II Prodrugs Type I prodrugs are bioactivated inside the cells (intracellularly). Type II prodrugs are bioactivated outside cells (extracellularly), especially
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- 17. Structures in Novel Classification: S.No. Category Drug Prodrug 1 TypeIA Dopamine L-DOPA 2 TypeIB Morphine Heroin 3 TypeIIA 5-amino salicyllic acid Sulfasalazin 4 TypeIIB Chloramphenicol Chloramphenicol succinate
- 18. Applications of Prodrugs: 1)Pharmaceutical Application: a)Masking Taste Or Odour b)Reduction Of Gastric Irritation c)Reduction in Pain at Site of Injection d) Enhancement of drug solubility and dissolution rate e) Enhancement of chemical stability 2) Pharmacokinetic Applications: a)Improvement of bioavailability b) Prevention of Presystemic metabolism c) Prolongation of duration of action d) Reduction of local and systemic toxicity of drugs e) Site specific drug delivery
- 19. Applications of Prodrugs continues.. 1)Pharmaceutical applications a) Masking Taste or Odour • Undesirable taste arises due to adequate solubility and interaction of drug with taste receptors. • It can be solved by lowering the solubility of drug or prodrug in saliva. • Eg: chloramphenicol palmitate is prodrug of chloramphenicol, which is practically tasteless due to its low aqueous solubility. It is hydrolysed to active chloramphenicol by the action
- 20. Masking taste or odour continues… Chloramphenicol Chloramphenicol palmitate (prodrug) (active drug) Pancreatic lipase
- 21. . b)Reduction of gastric irritation • Prodrugs are designed in such a way that they reduce gastric irritation. • Eg: Aspirin is a prodrug of salicylic acid which is designed to reduce the gastric irritation.
- 22. Reduction of gastric irritation continues Aspirin salicyllic acid (prodrug) (active drug)
- 23. . c) Reduction in Pain at Site of Injection • Pain caused by intramuscular injection is mainly due to the weakly acidic nature or poor aqueous solubility of drugs. • Eg: IM injection of antibiotic (clindamycin) and anti convulsant (phenytoin)was found to be painful due to poor solubility. So following prodrugs are produced which are as follows: clindamycin-2 dihydrogen phosphate of clindamycin and fosphenytoin (an aqueous soluble form) of phenytoin respectively.
- 24. Reduction in pain at site of injection continues… Eg: Drug Prodrug 1) Phenytoin Fosphenytoin 2) cindamycin cindamycin-2 dihydrogen phosphate
- 25. . d) Enhancement of drug solubility and dissolution rate The prodrug approach can be used to increase or decrease the solubility of a drug, depending on its ultimate use. The prodrug approach is also made useful for better gastrointestinal absorption. Eg: sulindac, a prodrug of sulindac sulfide being more water soluble with sufficient lipophilicity, makes this drug suitable for oral administration sulindac sulfide sulindac
- 26. . e) Enhancement of chemical stability The prodrug approach is based on the: a) modification of the functional group responsible for the instability or b) by changing the physical properties of the drug which results in the reduction of contact between the drug and the media in which it is unstable. Eg:, ampicillin molecule in concentrated solution generates polymeric species of ampicillin. By making hetacillin, a prodrug of ampicillin „ties up‟ the amine group inhibiting the auto aminolysis. note: Auto aminolysis occur due to capability of NH2 group of side chain to attach β lactam ring of other molecule
- 27. Enhancement of chemical stability continues… Ampicillin Hetacillin
- 28. . 2)Pharmacokinetic Applications a) Improvement of Bioavailablity ➢Enhancement of Oral Bioavailablity Various therapeutic agents such as water soluble vitamins, structural analogues of antibiotics like ampicillin , phenytoin and cardiac glycoside such as gitoxin suffers with poor gastrointestinal absorption. The prime cause of the poor absorption of these agents is their highly polar nature and poor lipophilicity eg: Dopamine was made useful by making its precursor L-Dopa(prodrug). Though LDopa is highly polar, it is actively transported through specific L–amino acid active transport mechanism and regenerates dopamine by decarboxylation.
- 29. Improvement of bioavailability continues… Eg: Drug Prodrug dopamine l-dopa
- 30. . b)Prevention of Presystemic metabolism : Following oral administration, a drug must pass through two metabolizing organs i.e., liver and gastrointestinal mucosa, before reaching the general circulation. Two types of drugs fall into this category. The first are drugs rapidly degraded by the acid condition of the stomach and The drugs of second category degrade due to enzymes present in the gastrointestinal mucosa and liver. Prodrugs may protect a drug from presystemic metabolism.
- 31. Prevention of presystematic metabolism continues…. Eg: Drug Prodrug Morphine Heroine
- 32. . c) Prolongation of duration of action Drugs with short half life require frequent dosing to maintain adequate plasma concentration of the particular drug. Prolongation of duration of action of a drug can be accomplished by the prodrug . Prodrug can be formed by two approaches- ❖ Control the release of the drug from complex ❖ Control the conversion of prodrug in to the parent drug. Eg: Drug Prodrug Estradiol Estradiol propionate
- 33. . d) Reduction Local and Systemic Toxicity of Drugs An important objective of drug design is to develop a moiety with high activity and low toxicity. Gastric irritation and ulcerogenicity associated with aspirin use due to presence of free carboxylic group. Esterification of aspirin(R = alkyl) and other nonsteroidal anti-inflammatory agents (NSAIDs) greatly suppresses gastric ulcerogenic activity.
- 34. . e) Site specific drug delivery After its absorption into the systemic circulation, the drug is distributed to the various parts of the body including the target site as well as the non-target tissue. These problems can be overcome by targeting the drug specifically to its site of action by prodrug design. The prodrug is converted into its active form only in the target organ/tissue by utilizing either specific enzymes or a pH value different from the normal pH for activation. Eg: Diethylstilbestrol diphosphate was designedfor site- specific delivery of diethylstilbestrol to prostatic carcinoma tissue.
- 35. CONCLUSION: Prodrug design is a part of the general drug discovery process, in which a unique combination of therapeutically active substances is observed to have desirable pharmacological effects. In human therapy prodrug designing has given successful results in overcoming undesirable properties like absorption, nonspecificity, and poor bioavailability and GI toxicity. Thus, prodrug approach offers a wide range of options in drug design and delivery for improving the clinical and therapeutic effectiveness of drug
- 36. REFRENCES: http://www.sciencedirect.com http://www.ncbi.nlm.nih.gov http://www.researchgate.net http://www.slideshare.net
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