Saurabh jain prodrug by sourabh jain best slide presentation

PRODRUG & ITS APPLICATIONS : 

PRODRUG & ITS APPLICATIONS PRESENTED BY: SOURABH JAIN M.PHARMA(P. CHEMISTRY) 2010MPCOO9

HISTORY : 

HISTORY In 1958 Albert initially coined the term pro drug and used it to refer to “A pharmacologically inactive compound that is transformed by the mammalian system into an active substances by either chemical or metabolic means.” This include both compounds that are desingned to undergo a transformation to yield an active substance and those were discovered by serendipity to do so. These two situation were distinguished by Harper in 1959 introduced the term : DRUG LATENTIATIONT: Refer to drugs that were specially designed to require bio activation. Types of prodrug to be produced depends on the specific aspect of the drug’s action that require improvement and the type of functionality that is present in the active drug.

PRO DRUGS : 

PRO DRUGS

PRODRUG CONCEPT : 

PRODRUG CONCEPT DRUG DRUG DRUG DRUG PROMOIETY PROMOIETY PROMOIETY BARRIER

PRODRUG TECHNOLOGY : 

PRODRUG TECHNOLOGY

PRODRUG CONCEPT : 

PRODRUG CONCEPT A prodrug is a pharmacological substance (drug) administered in an inactive (or significantly less active) form. Once administered, the pro drug is metabolised in vivo into an active metabolite, a process termed bio activation. A prodrug is an inactive derivative that will be converted to the active drug in vivo. Prodrug: A precursor (forerunner) of a drug. A prodrug must undergo chemical conversion by metabolic processes before becoming an active pharmacological agent.

PURPOSE OF PRODRUG DESIGN : 

PURPOSE OF PRODRUG DESIGN Improve absorption. Improve dissolution. Enhance bioavailability through Improving the solubility that may limit dissolution in the gastro-intestinal tract Increasing dissolution rate Improving permeability across biological membranes Control drug release. Avoid the first-pass metabolism/pre systemic metabolism via lymphatic absorption. Site specific delivery. Prolonged or shortened duration of action. Decrease toxicity. Improved patient compliance.

HARD AND SOFT DRUGS : 

HARD AND SOFT DRUGS HARD DRUGS: compounds that contain structural characteristics required for activity but are not susceptible to metabolism Increased efficiency by avoiding metabolism No toxic metabolites are formed however, less readily eliminated due to lack of metabolism. SOFT DRUGS: These are the opposite of pro drugs. These compounds are designed and synthesized as active compounds that readily undergo metabolic inactivation to nontoxic products Chemical transformation does not depend on the presence or relative amounts of metabolizing enzymes, an therefore less inter patient variability in activation. Such compounds are chemically unstable therefore storage of these compounds may present a problem.

CLASSIFICATION : 

CLASSIFICATION CARRIER-LINKED PRODRUGS: contain a group that can be easily removed enzymatically (such as an ester) to reveal the true drug. The group removed is pharmacologically inactive and nontoxic while the drug show its pharmacological action. connecting bond must be labile for efficient activation in vivo. BIOPRECURSORS: metabolized into a new compound that may itself be active or further metabolized to an active metabolite. Carrier-linked prodrugs can be further subdivided into: • Bipartate: composed of one carrier (group) attached to the drug. • Tripartate: carrier group is attached via linker to drug • Mutual prodrugs: two drugs linked together

CARRIER-LINKED PRODRUG : 

CARRIER-LINKED PRODRUG Drugs that are attached through a metabolically labile chemical linkage to another molecule designated as the “promoiety” The “promoiety” alters the physical properties of the drug to increase water or fat solubility or provide site-directed delivery. Increased absorption Injection site pain relief Elimination of unpleasant taste Decreased toxicity Decreased metabolic inactivation Increased chemical stability Prolonged or shortened action DRUG PROMOIETY CARRIER LINKAGE

CHLORAMPHENICOL : 

CHLORAMPHENICOL Chloramphenicol has low water solubility, May cause a pain at the site of injection. Drug begin to precipitate out of the solution and damage the surrounding tissues. Preparing drug with increased solubility in the administered solvent. Succinate ester was prepared to increase water solubility. Itself inactive as Anti bacterial agent. activation occur in plasma to active drug and succcinate ester. ester hydrolysis catalyses by esterage present in plasma.

CHLORAMPHENICOL : 

CHLORAMPHENICOL

MUTUAL PRODRUG : 

MUTUAL PRODRUG ESTRAMUSTINE (ANTINEOPLASTI AGENT) Used in the treatment of prostatic cancer. Estramustine consist of Phosphorylated steroid( 17 α Estradiol) linked to a Normustard [NH(CH2 CH2Cl)2]. Through a Carbamate linkage. The steroid portion of the molecule help to concentrate the drug in the prostate. Also has an anti androgenic effect on the prostate to slow the growth of the cancer cells. Hydrolysis occur to give normustard and CO2 normustard then act as a alkylating agent and exert a cytotoxic effect. phosphorylation to increase water solubility.

ESTRAMUSTINE : 

ESTRAMUSTINE

BIOPRECURSOR PRODRUG : 

BIOPRECURSOR PRODRUG ENZYMATIC CONVERSION SULINDAC (NSAID) Inactive as sulfoxide and must be reduced metabolically to the active sulfide. Administered orally, absorb in small intestine Prodrug form has benefit: reducing the GI irritation associated with the sulfide. Problem: precipitation of alternate metabolicpaths that may inactivate the compound,formation of solfone. Administration Absorb in small intestine Reduced to active species

SULINDAC : 

SULINDAC

CHEMICAL CONVERSION : 

CHEMICAL CONVERSION Hetcillin is a prodrug form ampicillin in which the amide nitrogen and the α amino functionalities have been allowed to react with acetone to give and imdazolidinone ring system. This decrease the basicity of α amino group and reduces protonation in the small intestine so that the agent is more lipophilic. Absorption of drug from the small intestine can be increased after oral dosing, and chemical hydrolysis after absorption regenerate ampicillin.

HETACILLIN : 

HETACILLIN H2O

PRODRUGS OF FUNCTIONAL GROUPSCARBOXYLIC ACIDS AND ALCOHOLS : 

PRODRUGS OF FUNCTIONAL GROUPSCARBOXYLIC ACIDS AND ALCOHOLS Prodrugs of agents that contain carboxylic acid or alcohol functionalities can be prepared by conversion to an esters. Most cpmmon because easy with which the ester can hydrolysed to give the active drug. Hydrolysis by esterase enzymes present in plasma and other tissues, capable of hydrolyzing a wide variety of ester linkage. Other enzymes: Esterase, hydrolase, Lipase, Cholesterol esterase, Acetylcholine esterase, Carboxy peptidase, Cholinesterase. To provide a wide range of lipophilic or hydrophilic properties to the drug. Manipulation of stearic and electronic properties of the promoiety allow control of the rate and the extent of hydrolysis.

CARBOXYLIC ACIDS AND ALCOHOLS : 

CARBOXYLIC ACIDS AND ALCOHOLS When desired to decrease water solubility, a non polar alcohol or carboxylic acid is choose as a prodrug moiety. So decrease hydrophilicity of the compound, Increased absorption. Decreased dissolution in the aqueous environment of the stomach. Longer duration of action. DIPIVEFRIN HCl Pro drug form of epinephrine in which catechol hydroxyl groups have been used to form ester linkage with pivalic acid. Agent used in open angle glaucoma. Increased lipophilicity cause easily move across the membrane of eye and achieve higher intraocular concentration. Hydrolysis in the cornea, conjunctiva and aqueous humor to generate active drug, epinephrine. pivilic acid as a promoity increase the stearic bulk around the ester bond which slow the ester hydrolysis.

DIPIVEFRIN HCl : 

DIPIVEFRIN HCl esterase

CHLORAMPHENICOL PALMITATE : 

CHLORAMPHENICOL PALMITATE Number of drugs have an unpleasant taste when given orally. These drugs are dissolved in mouth and interact with taste receptors to give bitter sense. Useful specially in padiatric patient, so with reduced solubility does not dissolve to any appreciable extent in the mouth . Chloramphenicol palmitate( antibacterial action) Chloramphenicol has bitter taste.

CHLORAMPHENICOL PALMITATE : 

CHLORAMPHENICOL PALMITATE

AMINES : 

AMINES Derivatization of amines to amide as pro drug not used because of the high chemical stability of the amide linkage and lack of amidase enzymes necessary for hydrolysis. Amines incorporated into peptide linkages which serve to increase cellular uptake by the use of an amino acid transporter. Amino acid then cleaved by specific peptide enzymes. Mannich bases (hetacillin)

HETACILLIN : 

HETACILLIN H2O

AZO LINKAGE : 

AZO LINKAGE Amines also incorporated into Azo linkage to produce a prodrug. PRONTOSIL( antibacterial) Inactive in vitro and active in vivo. converted by Azo Reductase enzymes to sulfonamide. SULFASALAZINE used in treatment of ulcerative colitis. Reduced by Azo Reductase and release amino salicylic acid which has an anti inflammatory effect on the colon and sulfapyridine. Prevent systemic absorption before the active site.

PRONTOSIL : 

PRONTOSIL Azo reductase

SULFASALAZINE : 

SULFASALAZINE Azo reductase

CARBONYL COMPOUNDS : 

CARBONYL COMPOUNDS Involved derivatives in which the sp2 hybridised carbonyl carbon is converted to an sp3 hybridized carbon attached to two hetero atoms, such as O, N, S. METHAMINE Methamine release formaldehyde in urine which act as anti bacterial agent by reacting with nucleophile present in bacteria. In a form of enteric-coated capsules to protect it from premature hydrolysis in the acidic environment of the stomach. So prevent systemic formaldehyde release and reduces toxicity.

METHAMINE : 

METHAMINE Methamine Formaldehyde

BIOPRECURSOR PRODRUGS : 

BIOPRECURSOR PRODRUGS Bioprecursor prodrugs do not contain a carrier or promoiety but rather contain a latent functionality that is metabolically or chemically transformed to the active drug molecule. These types of activation involved: Oxidative activation. Reductive activation. Phosphorylation. some times chemical activation. Among them oxidative activation commonly seen because of the presence of the abundance of oxidizing enzymes in the body. e.g. Isoenzyme cytochrome P- 450 can oxidise a wide variety of functionalities.

NABUMATONE(NSAID) : 

NABUMATONE(NSAID) NSAID produces stomach irritation, due to presence of acidic functionality in these agents. The carboxylic acid functionality found in these agent in un-ionised form in the highly acidic environment of the stomach. Highly lipophilic and may pass in to the cells of the gastric mucosa . The intracellular PH of these cells is more basic than that of the stomach lumen, and the NSAIDs become ionized. Result in backflow of H+ from the lumen into these cells which cause cellular damage.

NABUMATONE(NSAID) : 

NABUMATONE(NSAID)

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