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Questions and Answers

What is the rate of absorption for the drug mentioned?

70-80%

50-60%

100%

98-99% (correct)

Which of the following components results in hydrolysis activation of Drug—X?

Hydroxyl (OH) group

Carboxyl (COOH) group (correct)

Tert-Butyl (t-Bu) group

N+ group

What characteristic of Drug—X allows it to cross the blood-brain barrier?

Size of the molecule

Electropositive charge

Lipophilic nature (correct)

Hydrophilic nature

What happens to Drug—X if oxidation occurs before it enters the brain?

It cannot cross the blood-brain barrier. Signup and view all the answers

What is the primary function of an imine (Schiff base) prodrug mentioned in the content?

To hydrolyze into GABA inside the brain Signup and view all the answers

Which form of Drug—X is involved in passive diffusion into the brain?

The lipophilic carrier form Signup and view all the answers

Which of the following structures represents pivampicillin?

R = H, R' = t-Bu Signup and view all the answers

Which type of prodrug is characterized by bioreduction in its activation process?

Reductive carrier-linked prodrugs Signup and view all the answers

What is released from the drug within 15 minutes?

Ampicillin Signup and view all the answers

What is parecoxib sodium derived from?

Valdecoxib Signup and view all the answers

In the context of prodrugs, what is the relevance of carbonyl compounds?

They serve as precursors to various prodrug analogs. Signup and view all the answers

What is the role of the NH2, OH, or COOH group in XH of the drug?

To serve as electron donor and acceptor sites Signup and view all the answers

Which structural feature is common to prodrugs of sulfonamides?

Presence of a sodium ion Signup and view all the answers

What is the main goal of using prodrugs like those discussed in the content?

To improve physicochemical properties and bioavailability Signup and view all the answers

Which of the following best describes imines and oximes in the context of prodrugs?

They are analogs of carbonyl compounds used in drug synthesis. Signup and view all the answers

What distinguishes bipartate prodrugs in the provided content?

They consist of two components that are released in the body. Signup and view all the answers

What is the primary purpose of prodrugs in the context of antihypertensive medications?

To reduce the number of doses needed per day Signup and view all the answers

Which of the following prodrugs has been mentioned to provide antipsychotic activity for about a month?

Haloperidol decanoate Signup and view all the answers

What is a significant reason for using prodrugs to minimize toxicity?

To reduce systemic side effects due to rapid metabolism Signup and view all the answers

Which of the following statements about clindamycin palmitate is true?

It is a prodrug designed to be less bitter and more palatable. Signup and view all the answers

What is one of the challenges that prodrugs aim to address regarding administration?

To eliminate peaks and valleys of fast release Signup and view all the answers

Which characteristic is a common feature of long-chain fatty acid esters used as prodrugs?

They provide slow and prolonged release of medication. Signup and view all the answers

What is a key benefit of using prodrugs like dipivaloylepinephrine compared to their active counterparts?

Reduced systemic and ocular side effects Signup and view all the answers

Why might a prodrug be preferred over its active form for administration?

To reduce the risk of irritation or toxicity at the site of administration Signup and view all the answers

What type of reaction can be used with carboxylic acid drugs in the described delivery system?

Self-immolative reaction Signup and view all the answers

Which feature makes β-lactams ineffective in crossing the blood-brain barrier?

Too hydrophilic Signup and view all the answers

What role does esterase play in the drug delivery mechanism described?

It catalyzes hydrolysis Signup and view all the answers

In the redox drug delivery example, what type of delivery concentration is emphasized for β-lactams?

High concentrations Signup and view all the answers

Why might antibody generation in the brain be considered insignificant?

Limited blood-brain barrier permeability Signup and view all the answers

What is the main characteristic of the drug delivery method involving a carboxylic acid?

It utilizes self-immolative reactions Signup and view all the answers

What is one of the limitations of β-lactams that affects drug delivery to the brain?

They possess high hydrophilicity Signup and view all the answers

Which other molecular characteristics could potentially improve drug delivery across the blood-brain barrier?

Decrease in size and lipophilicity Signup and view all the answers

What is the role of liver homogenates in the activation of cyclophosphamide?

They provide cytochrome P450 enzymes for activation. Signup and view all the answers

What is a major component of the conversion process of cyclophosphamide?

Phosphoramidase Signup and view all the answers

Which of the following is a structural change that occurs during the activation of cyclophosphamide?

Changing from a phosphate group to a hydroxyl group Signup and view all the answers

Cyclophosphamide can be described as having which of the following characteristics?

It requires specific liver enzymes for its activation. Signup and view all the answers

What is a likely consequence of cyclophosphamide not being activated?

Loss of pharmacological activity Signup and view all the answers

Which of the following compounds is not explicitly involved in the activation mechanism of cyclophosphamide?

Chlorine Signup and view all the answers

Cyclophosphamide's effectiveness is primarily linked to which type of biological activity?

Anticancer activity Signup and view all the answers

What happens to cyclophosphamide upon undergoing P450-mediated activation?

It transforms into a form that can damage DNA. Signup and view all the answers

What is the primary benefit of utilizing glucose metabolism in patients with ischemic heart disease?

It requires less oxygen consumption. Signup and view all the answers

What is the role of arylglyoxylic acids in metabolism?

Stimulate pyruvate dehydrogenase. Signup and view all the answers

How is oxfenicine metabolized in the heart?

It is transaminated to arylglyoxylic acid. Signup and view all the answers

What is the main purpose of developing a macromolecular delivery system for sulfapyridine?

To prevent side effects caused by sulfapyridine. Signup and view all the answers

What happens to sulfapyridine in the macromolecular delivery system?

It remains attached to the polymer and is not released. Signup and view all the answers

What condition is sulfasalazine primarily used to treat?

Ulcerative colitis. Signup and view all the answers

What is a likely result of the anaerobic cleavage of sulfasalazine by bacteria?

Release of sulfapyridine. Signup and view all the answers

How does poly(vinylamine) contribute to the treatment method discussed?

It serves as a carrier for sulfapyridine, preventing its release. Signup and view all the answers

Study Notes

Prodrugs and Drug Delivery Systems

Prodrugs are pharmacologically inactive compounds that are converted to an active drug by metabolic biotransformation.
Ideally, the conversion to the active drug occurs as soon as the desired goal for designing the prodrug is achieved.
Prodrugs are inactive, requiring metabolism to become active.
Soft drugs are active and use metabolism to promote excretion.
Pro-soft drugs need metabolism to be converted to a soft drug
Prodrugs are used to improve aqueous solubility, absorption, distribution, and site specificity; to prevent rapid metabolism to avoid first-pass effect; to make less toxic, or to improve patient acceptability (remove unpleasant taste/odor, reduce gastric irritation), or improve drug formulation (convert gas/volatile liquids to solids).

Drug Discovery: Drug Design and Development

Drug design and development includes optimizing target interaction and optimizing access to the target.

Types of Prodrugs

Carrier-linked prodrugs: The active drug is covalently linked to an inert carrier/transporter moiety. Increased lipophilicity is achieved due to the carrier. The active drug is released by hydrolytic cleavage (chemically or enzymatically).
- Bipartite: One carrier attached to the drug.
- Tripartite: Carrier is connected to a linker which is connected to the drug.
Bioprecursors: These are inert molecules obtained by chemical modification of the drug, but do not contain a carrier. These have the same lipophilicity as the parent drug and are bioactivated (generally by redox biotransformation-only enzymatically).
Mutual prodrugs: Two pharmacologically active agents coupled together, with each acting as a carrier for the other.

Classification of Prodrugs (Further Detail)

Carrier-linked prodrugs (details): Active drug is covalently linked to an inert carrier/transporter moiety. Enhanced lipophilicity is due to the attached carrier. The active drug is released by hydrolytic cleavage.
Bioprecursors: These molecules have a chemical modification of the drug, but do not have a carrier. The lipophilicity is the same as the parent drug and are activated by redox biotransformation (enzymatically).
Mutual prodrugs: Two pharmacologically active agents are coupled together, with one molecule acting as a carrier for the other.

Utility of Prodrugs

Increased Aqueous Solubility: Increasing water solubility allows for injection in smaller volumes.
Improved Absorption and Distribution: Increased lipid solubility enables better absorption through membranes.
Site Specificity: A drug with high specificity will only produce the desired therapeutic effect, not other physiological changes, and ensures targeted action with minimal side effects.
Stability (First-Pass Effect): Prevents rapid metabolism to avoid inactivation.
Prolonged Release: Gives a slower, steady release of the drug.
Minimizing Toxicity: The prodrug can be less toxic until it reaches the site of action.
Improved Patient Acceptability: This involves removing unpleasant tastes/odors or reducing gastric irritation.
Formulation Improvement: Converting gas or volatile liquids into stable solids.

Strategies for Prodrug Design

Carriers: Inert molecules attached to the active drug through metabolically labile linkages. They improve desirable properties like increased lipid/water solubility and better targeting to the target site.
- Specifiers: Parts of the prodrug that direct the drug to the target site.
Linkers: A releasable spacer incorporated between the specifier/carrier and the parent drug.
Classification of linkers: Electronic cascade linkers and Cyclization linkers.

Applications of Prodrugs

Improved patient acceptability (taste and odour improvements, reduction of gastric irritation).
Enhancing drug solubility.
Enhancing drug absorption and distribution.
Site specific drug delivery.
Sustained drug action

Mechanisms of Prodrug Activation

The most common activation reaction for carrier-linked prodrugs is hydrolysis.
Hydrolysis rate can be controlled by alkyl group placement relative to the carbonyl group to increase steric hindrance and retard the rate of hydrolysis.

Ideal Drug Carriers

Protect the drug until it reaches the site of action.
Localize the drug at the site of action.
Allow for release of the drug.
Minimize host toxicity.
Biodegradable, inert, and non-immunogenic.
Easily prepared and inexpensive.
Stable in the dosage form.

Carrier Linkages for Various Functional Groups

Esters are the most common prodrug from for alcohols and carboxylic acids.
Esterase enzymes are ubiquitous, helping to control ester stability.

Prodrugs for Alcohol-Containing Drugs

Ester analogs can affect lipophilicity or hydrophilicity.
pKa effects: Attaching different substituents can change the pKa of the drug moiety and thus alter its water solubility.

Prodrugs for Improved Solubility and Dissolution Rate

Dissolution is the rate-limiting step in drug absorption.
Prodrugs can be designed to increase the rate of dissolution for improved drug delivery.

Prodrugs for Increased Water Solubility

Esterification is a common way to enhance the water solubility of drugs.
Amidation can also be used to improve water solubility.

Prodrugs for Improved Absorption and Distribution

Prodrugs can be designed to improve oral absorption. Increasing lipophilicity facilitates membrane penetration and better absorption.

Prodrugs for Stability (First-Pass Metabolism)

Prodrugs can circumvent first-pass metabolism by changing the drug into a form that resists metabolism by enzymes in the liver or gastrointestinal tract.

Prodrugs for Slow and Prolonged Release

Prodrugs of drugs can improve the rate and duration of drug release and reduce the need for frequent administrations.

Prodrugs to Minimize Toxicity

Prodrugs can reduce toxicity by converting the drug into a less toxic form until it reaches the desired target site..

Classification of Prodrugs (Continued)

Examples of prodrugs: Benorylate, Emcyt.

Prodrugs to Minimize Toxicity (continued)

Ester derivatives of aspirin can reduce gastric irritation.

Prodrugs to Increase Patient Acceptance

Prodrugs can change the taste or odor profile of a drug.

Prodrugs to Eliminate Formulation Problems

Convert gaseous or volatile liquid drugs to solid forms.

Areas of Improvement for Prodrugs

Improvements to site specificity.
Protection from biodegradation.
Minimizing side effects.

Macromolecular Drug Delivery

Addresses short-comings of conventional drug delivery systems.
Macromolecules (polymers, proteins, lectins, antibodies, or cells) are used to deliver drugs to specific sites.
Absorption/distribution properties depend on the carrier, not the drug.
Reduces interactions with other tissues or enzymes, thus improving a drug's therapeutic index.

Disadvantages of Macromolecular Delivery Systems

Macromolecules may not be well absorbed
Different methods of administration may be necessary.
Immunogenicity issues

Macromolecular Drug Carriers (Synthetic Polymers)

Aspirin linked to a polymer carrier has similar potency to aspirin but with reduced toxicity.

Steric Hindrance by Polymer Carrier

Polymer backbones can sterically hinder the release of the testosterone, affecting its therapeutic effectiveness.
Adding spacer arms can address these problems, leading to better performance.

Poly(a-Amino Acid) Carriers

Polymers based on amino acids have shown promise for controlled release of drugs, as seen with Norethindrone.

General Site-Specific Macromolecular Drug Delivery System

Polymer chains with solubilizers and homing devices can improve drug delivery.

Site-Specific Delivery of a Nitrogen Mustard

Combining a water-soluble component with a polymer carrier can increase the therapeutic index, demonstrating improved effectiveness.

Tumor Cell Selectivity

Tumor cells quickly absorb proteins, and those proteins are then broken down, leading to drug release inside the tumor cells.

Antibody-Targeted Chemotherapy

The use of antibodies for drug delivery to cells allows selective drug delivery to target cells.
Calicheamicin (in conjunction with antibodies) shows no immune response and is not released non-enzymatically.

Calicheamicin

A highly potent DNA-damaging cytotoxic natural product.
Mechanism of action involves DNA scission.
Independent of cell cycle progression.

Tripartate Drugs (Self-Immolative Prodrugs)

A bipartate prodrug may be ineffective because of the linkage being too labile or too stable.
A tripartate prodrug (versus bipartate) changes the attachment of the carrier from the drug to the linker, allowing more linker choices and separating the cleavage site from the carrier, thus improving performance.
The linker-drug bond must cleave spontaneously (self-immolative) after the carrier-linker bond is broken.

Typical Approach

The typical way to cleave and activate the drug is to use an esterase, which cleaves rapidly to release the drug component.

Tripartate Prodrugs of Ampicillin

Ampicillin has poor oral absorption.
Various ampicillin esters were too stable in humans because the thiazolidine ring was thought to sterically hinder the esterase.

Pivampicillin

Pivampicillin is a pivaloyloxymethyl ester of ampicillin, a prodrug that enhances oral bioavailability due to its greater lipophilicity.

Hydrolysis Deactivated/Activated

A hydrophilic drug can be made lipophilic for passive absorption into the brain. An active transport mechanism can be used to take the drug out.
A change in the drug's oxidation state can affect its ability to cross the blood-brain barrier.

When the Drug is a Carboxylic Acid

When the drug is a carboxylic acid, a self-immolative reaction can be used for activation.

Example of Redox Drug Delivery

B-lactams are too hydrophilic to cross the blood-brain barrier effectively.
Higher concentrations of β-lactams can be delivered to the brain.

Tripartate Prodrug for Delivery of Antibacterials

Permeases are bacterial transport proteins for peptides.
Permeases allow the diffusion of a specific molecule in or out of a cell.

Mutual Prodrugs

The carrier linked to the drug is a synergistic drug.

Ideal Mutual Prodrugs

Both components in the mutual prodrug are well absorbed.
Components are released together and quantitatively.
Maximal effect occurs at a 1:1 ratio.
Components have similar distribution/elimination patterns.

Bioprecursor Prodrugs

Carrier-linked prodrugs often use hydrolytic activation.
Bioprecursor prodrugs use oxidative or reductive activation.
Metabolically-activated alkylating agents are types of bioprecursor prodrugs.

Protonation Activation of Omeprazole

Cimetidine and ranitidine reduce gastric acid secretion by antagonizing the H2 receptor.
Omeprazole is another example of proton pump inhibition.
The lead compound (a thioamide) was found in a random screen.
Modifications were aimed at reducing toxicity.

Lead Modifications (continued)

Modifications of lead compounds were further developed.
Sulfoxide is a more potent compound, but it blocked iodine uptake.

Lead Modifications (continued)

Modifications to the lead compound are continuing.
Modification of 8.64 lead compound reduced iodine blockage.
Picoprazole is an inhibitor of H+,K+-ATPase.
Electron donating groups in the pyridine ring improved the inhibition of H+,K+-ATPase's function.
Omeprazole (a lead compound) is useful.

Formation of Omeprazole

A lower pKa for the pyridine ring on omeprazole allows it to cross cell membranes and be protonated.
Reaction gives a covalent attachment.
Omeprazole also inhibits carbonic anhydrase isozymes.

Hydrolytic Activation

Hydrolysis is a mechanism of prodrug activation, needed when a compound needs additional activation.
Leinamycin is an example of a prodrug needing additional activation via hydrolysis.

Elimination Activation

Leflunomide is an example of an elimination prodrug, used in the treatment of rheumatoid arthritis.
Leflunomide blocks dihydroorotate dehydrogenase to block pyrimidine biosynthesis..

Oxidative Activation

Examples include alprazolam and triazolam.
N-dealkylation, is a form of oxidative activation.

O-Dealkylation

Phenacetin is an example of a drug whose analgesic activity results from O-dealkylation to acetaminophen.

Oxidative Deamination

Neoplastic cells have high phosphoramidase concentrations, requiring modifications of nitrogen mustards to activate selectively within those cells.
Cyclophosphamide, requiring P450 oxidation, is an example.

N-Oxidation

Pralidoxime is an antidote to nerve poisons.
Reduction of the ring of Pralidoxime increases permeability into the CNS, leading to improved outcomes because it maintains a useful concentration of drug within the brain.

Prodrugs for (Increased) Site Specificity

Prodrug system can be designed to get drugs into the CNS and prevent efflux.
Drug delivery through attachment of a hydrophilic drug to a lipophilic carrier with a dihydropyridine group in a prodrug that actively crosses into the target tissue; e.g, the brain.

Mechanism of Acetylcholinesterase

Mechanism of enzyme reaction.

Inactivation of Acetylcholinesterase

Diisopropyl phosphorofluoridate used to prevent degradation of acetylcholine.

Reactivation of Inactivated Acetylcholinesterase

Proparidoxime reactivation of inactivated acetylcholinesterase.

Temporary Inhibition of Acetylcholinesterase

Neostigmine used to enhance cholinergic activity in skeletal muscle.
Neostigmine acts as a temporary inhibitor of acetylcholinesterase.

Reversible Inhibitors of Acetylcholinesterase

Donepezil and tacrine are reversible inhibitors used for Alzheimer's disease.
These inhibitors enhance neurotransmission involving memory functions.

S-Oxidation

Briefeldin A is an example of an agent whose oral bioavailability is improved after S-Oxidation.

Aromatic Hydroxylation

Cyclohexenones used as prodrugs for catechols.

Alkene Epoxidation

Carbamazepine converted to an active anticonvulsant via epoxidation.

Transamination

Pyruvate dehydrogenase stimulation leads to a change in myocardial metabolism, switching from fatty acid use to glucose use.
Glucose metabolism improves oxygen consumption.

Arylglyoxylic Acids

Arylglyoxylic acids stimulate pyruvate dehydrogenase but have a short duration of action.

Reductive Activation (Azo Reduction)

Sulfasalazine used for ulcerative colitis.

Reductive Activation (Continued)

Sulfapyridine is a more potent analog than sulfasalazine.

Azide Reduction

Vidarabine is rapidly deaminated by adenosine deaminase.

Sulfoxide Reduction

Sulindac inactive in vitro, but the sulfide is active in vivo.

Disulfide Reduction

Thiamin used in the brain and has issues with dissolving and absorption within the CNS.

Primaquine

Primaquine, an antimalarial drug, can have its toxicity diminished by molecular modifications.

Nitro Reduction

Mechanism-based inactivator of thymidylate synthase.

Nucleotide Activation

6-mercaptopurine, a prodrug used for leukemia

Phosphorylation Activation

Acyclovir converted to an active form through phosphorylation to be utilized within cells.

Antibody-Directed Enzyme (ADEPT) /Antibody-Directed Abzyme Prodrugs Therapy (ADAPT)

Strategies for site-specific delivery of drugs to cancerous tissue.

Enzymes: ADEPT /ADAPT

Strategies for site-specific delivery of drugs to cancerous tissue.

Gene-Directed Enzyme Prodrug Therapy (GDEPT)

Using a gene encoding a prodrug-activating enzyme expressed in the target.
Expression occurs via tumor-selective promoters or viral transfection.

Other Aspects of Prodrugs

Summary notes on protecting L-dopa from peripheral degradation, the concept of ideal mutual prodrugs, and other prodrug approaches.

Ideal Drug Carriers (Continued)

Protect the drug until it reaches the site of action.
Localize the drug at the site of action.
Allow for release of the drug.
Minimize host toxicity.
Be biodegradable, inert, and non-immunogenic.
Be easily prepared and inexpensive.
Stable in the dosage form.

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