Pharmacology Quiz on Prodrugs and Drug Development

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Questions and Answers

What is a characteristic of enantiomers?

They contain a stereogenic center. (correct)

They always exist as a single form.

They have different chemical properties.

They are superimposable on each other.

What defines structural isomers?

Compounds that possess identical connectivity.

Compounds with the same molecular formula but different structures. (correct)

Isomers that differ only in spatial arrangement.

Isomers that have the same functional groups in the same arrangement.

What does partial antagonism imply?

100% receptor occupancy guarantees a full response.

Full agonism is present at high receptor occupancy.

The intrinsic efficacy is between 0 and 1. (correct)

There is a complete absence of response at receptor occupancy.

Which statement describes chemical antagonism?

Two substances create an inactive compound when combined. Signup and view all the answers

What is a racemic mixture?

A 50:50 mixture of enantiomers. Signup and view all the answers

What does a positive LogP value indicate about a compound's distribution?

More of the compound is present in the organic phase compared to the aqueous phase. Signup and view all the answers

Which process does not require energy for drug movement across cell membranes?

Passive aqueous diffusion Signup and view all the answers

What is the purpose of altering solubility in drug development?

To improve membrane permeability Signup and view all the answers

What is Fick's law of diffusion primarily concerned with?

The rate of drug absorption based on concentration differences. Signup and view all the answers

How does the ionization of weak acids and bases affect drug absorption?

Unionized forms are typically more lipid soluble and can easily diffuse across membranes. Signup and view all the answers

In the drug development process, what primarily occurs during the 'discovery' phase?

Understanding drug targets and treatment indications Signup and view all the answers

What is one key factor that complicates drug development due to funding?

Researchers must remain independent Signup and view all the answers

What role do special carriers play in drug movement across cell membranes?

They facilitate the movement of large molecules like peptides and glucose. Signup and view all the answers

What does a LogP value of 0 indicate about a compound's partitioning between two phases?

The compound is present in equal concentrations in both phases. Signup and view all the answers

Which of the following drugs is derived from natural sources?

Paclitaxel Signup and view all the answers

What is a primary feature of passive (simple) diffusion?

It is influenced by the permeability of the membrane and concentration gradients. Signup and view all the answers

What is one of the primary reasons for regulatory approval of pharmaceuticals?

To verify the safety and efficacy of medications Signup and view all the answers

What is the significance of Lipinski's Rule of 5 in drug development?

It helps predict the drug's absorption and permeability Signup and view all the answers

What can be inferred about drugs that are weak acids or bases in relation to tissue pH?

Tissue pH can influence whether these drugs become predominantly ionized or unionized. Signup and view all the answers

Which of the following is true about the rabies vaccine developed by Louis Pasteur?

It is based on an attenuated virus formulation Signup and view all the answers

What challenge do companies face concerning patenting in drug development?

Deciding if a product should be patented or kept secret Signup and view all the answers

What was one of the first controlled clinical trials conducted, and what substance was tested?

Patulin in 1943 Signup and view all the answers

What factor influences the slow release of active agents in drug formulations?

Masking polar groups Signup and view all the answers

What happens to the selectivity of a drug as its concentration increases?

Selectivity decreases because it binds to more targets. Signup and view all the answers

Which term best describes the ability of a drug to bind to its target?

Affinity Signup and view all the answers

What is the intrinsic efficacy of a full agonist?

1 Signup and view all the answers

How do enzymes increase the rate of chemical reactions?

By remaining unchanged after the reaction. Signup and view all the answers

What defines the potency of a drug?

The dose required to achieve an effect. Signup and view all the answers

Which of the following best describes the role of the active site in enzymes?

It provides a specific surface for substrate binding. Signup and view all the answers

What is the effect of an allosteric modulator on a receptor?

It alters the receptor's activity without binding to the primary site. Signup and view all the answers

What is indicated by the IC50 value of a drug?

The drug concentration needed to occupy 50% of target proteins. Signup and view all the answers

Which type of binding occurs at the orthosteric site of a receptor?

Both agonist and antagonist binding. Signup and view all the answers

Which mechanism explains how enzymes lower activation energy?

By offering alternative reaction pathways. Signup and view all the answers

Which component is NOT part of the cytochrome P450 system?

Glucose-6-phosphate Signup and view all the answers

What is the primary function of glucuronidation in drug metabolism?

Add polar groups to enhance excretion Signup and view all the answers

What role does glutathione play in drug metabolism?

Facilitates conjugation of drugs to reactive electrophiles Signup and view all the answers

Which statement about codeine metabolism is correct?

Involves genetic polymorphisms affecting analgesia Signup and view all the answers

What happens during paracetamol overdose?

Glutathione stores are depleted leading to cell damage Signup and view all the answers

How are inactive prodrugs activated in the body?

By specific cytochrome P450 enzymes Signup and view all the answers

Which of the following statements regarding drug elimination is false?

All drugs are eliminated exclusively through the kidneys. Signup and view all the answers

What is a key characteristic of phase II metabolic reactions?

They generally create more polar substances for easier excretion. Signup and view all the answers

Which drug is primarily converted by CYP2D6 into an active metabolite?

Tamoxifen Signup and view all the answers

Which enzyme is primarily responsible for catalyzing glucuronidation?

UGT Signup and view all the answers

Study Notes

Prodrugs

Prodrugs are inactive forms of drugs that are administered and metabolized to give the active form
Uses for prodrugs include:
- Altering drug solubility
- Improving membrane permeability
- Slowing release of active agent
- Masking drug toxicity
- Masking drug side effects

Lipinski's Rule of 5

Used for predicting druglikeness of compounds

Core Pharmacology Concepts

Pharmacokinetics -- refers to the movement of drugs in the body
Pharmacodynamics -- refers to the effects of drugs on the body

Drug Development Phases

Discovery
- Understanding drug target and treatment indication.
- Finding lead molecule using natural products, ligand-based design, or structure-based design.
- Understanding disease, drug target, and lead compound.
Development
- Testing from cells to animals to humans.
- Pre-clinical pharmacology (PD + PK).
- Pre-clinical toxicology.
- Clinical trials (humans).
Regulation
- TGA (Therapeutic Goods Administration) approval
- PBS (Pharmaceutical Benefits Scheme) approval

Conflict of Interest in Drug Development

Scientists need to remain independent, even though funding is needed for projects
Honest, open and transparent scientific practices are necessary
Disclosure of all interactions with potential sources of conflicts of interest is essential

Regulatory Approval

All pharmaceuticals must be registered in OECD countries before they can be marketed
Each country has its own regulatory authority
Drug companies must apply for market authorization in each jurisdiction

Challenges in Drug Development

Patentability of drug
Efficacy and safety testing
Regulation for new drug products

Sources of Drugs

Plant-derived sources:
- Paclitaxel is extracted from the Pacific yew tree
- Dauno- and Doxorubicin are extracted from bacteria found in Castel del Monte in Italy
Molds: Penicillin
Seeds: Ricin from the castor plant
Viruses: Variola virus

Smallpox

Edward Jenner developed the first smallpox vaccine in 1796
WHO successfully eradicated smallpox in 1980

Rabies

Rabies is a zoonotic viral disease that is spread through bites
Almost 100% fatal once symptoms appear
Louis Pasteur and Emile Roux developed the first rabies vaccine in 1885

Vitamin C Deficiency

Scurvy results from Vitamin C deficiency
James Lind demonstrated in 1747 that citrus fruit helped prevent scurvy
The first running clinical trial was conducted by Lind

Development of Clinical Trials

The first double-blind clinical trial was conducted in 1943 for Patulin
The first randomized controlled trial of streptomycin for TB was conducted in 1946

LogP

LogP describes lipophilicity and predicts movement in cell membranes
LogP = Log10 Partition Coefficient
LogP = 0 when equal amounts of a compound are distributed in both organic and aqueous phases.
Positive LogP values indicate increased affinity for the organic phase.

Movement of Drugs Across Cell Membranes

Passive (simple) diffusion: Movement across the membrane via pores or by dissolving in the cell membrane. This follows concentration gradient
Facilitated diffusion: Some compounds move across the membrane by combining with solute carrier (SLC) transporter proteins (facilitated diffusion) e.g., glucose
Active transport: Movement against concentration gradient and requires energy, often mediated by carrier proteins
Special carriers: Peptides, amino acids, and glucose
Pinocytosis: E.g., Vit B12 (intrinsic factor essential for absorption)

Fick's Law of Diffusion

Simple diffusion is governed by the permeability of the membrane and the drug concentration gradient
When the thickness of the barrier is small and/or the permeability, surface area or the starting concentration are high relative to the receiving compartment then flux across membrane is favored.

Drug Absorption: Role of Drug Ionization

Many drugs are either weak acids or weak bases, and can be predominantly in ionized or unionized form depending on the pH of the environment
The unionized forms of weak acids (HA) and weak bases (B) are the lipid soluble forms

Tissue pH and Drug Disposition

Tissue pH can affect drug disposition

Drug Metabolism

Phase I reactions: Oxidation, reduction, hydrolysis
Phase II reactions: Conjugation, build, add, result in more polar, more likely to be excreted
Glucuronidation: Most common Phase II reaction
Glutathione: Reactive species detoxification

CYP450 system

Responsible for metabolism of many drugs
Located in the smooth endoplasmic reticulum
Requires NADPH, O2 as cofactors
Some drugs are metabolized by more than one CYP
Some drugs are metabolized to active metabolites
Some drugs are metabolized to toxic metabolites

Codeine

Converted into morphine by CYP2D6
Genetic polymorphisms exist:
- Poor metabolizers -- poor analgesia
- Rapid metabolisers -- strong opioid effects
- Ultra-rapid metabolisers (more common in people of Middle Eastern, Mediterranean, sub-Saharan African, Northern European, and Chinese descent)

Excretion and Elimination

Elimination is achieved through renal and metabolic biotransformation
Renal: glomerular filtration, active tubular secretion, tubular reabsorption
Others (minor): pulmonary, sweat, saliva, hair, breast milk

Drug Elimination

Total clearance (Cltotal) = Cl renal + Cl hepatic (liver) + Cl....

Specificity and Selectivity

No drug acts with complete specificity -- hence side effects
Selectivity = ability of given drug concentration to produce one effect over another
Higher concentrations -- lower selectivity

Affinity

Ability of a drug to bind to a target
Quantified as IC50 (Concentration of drug required to occupy 50% of target proteins)

Intrinsic Efficacy

Ability of a drug to elicit/produce a response
Maximal effect drug can produce on specific tissue as fraction of maximal effect of a full agonist on that tissue
Full agonist -- intrinsic efficacy = 1
Antagonist -- intrinsic efficacy = 0
Partial agonist -- 0-1

Potency

Concentration of a drug that causes a specified effect
More potent -- produce effect at lower concentration

Orthosteric and Allosteric Binding

Orthosteric binding site: Recognized and bound by the endogenous molecule on the receptor
Allosteric binding site: A different location on the receptor
Agonists and antagonists bind to the orthosteric site.
Modulators bind to the allosteric site.

Enzymes

Biocatalysts that speed up reactions
Mostly proteins
28% of drug targets are enzymes

Enzyme Structure

Enzymes provide:
- Reaction surface (active site)
- Suitable environment for reaction to occur

How Enzymes Provide Suitable Surface and Environment

Enzymes are specific for their substrate and have absolute selectivity.

Lowering Activation Energy

Activation energy is the energy needed to bring reactants to a transition state.
Enzymes lower activation energy by positioning substrates correctly and facilitating bond re-arrangements.

Binding Energy

Energy derived from enzyme-substrate interactions.
This energy lowers the activation energy of the reaction.

Receptor Pharmacology

A drug may bind to the same receptor to achieve a different effect.
Acetylcholine will contract bronchial smooth muscle while salbutamol will relax it

Partial Antagonism

A drug that exhibits partial agonism has an intrinsic efficacy between 0 and 1
Not 100% response even at 100% receptor occupancy

Chemical Antagonism

When 2 substances combine to form an inactive compound

Isomers

Different compounds with the same molecular formula
Structural Isomers: Structural differences
- Functional isomers -- differ in functional group
- Tautomeric isomers -- differ by the displacement of 1 hydrogen atom
- Positional isomers -- functional group in different arrangement
Stereoisomers: Same connectivity but differ in arrangement of atoms in space
- Enantiomers -- non-superimposable mirror images
- Diastereoisomers -- not mirror images

Enantiomers

Contain a stereogenic (chiral) centre
Non-superimposable mirror image
50:50 mixture of enantiomers is called a racemic mixture
Pair of enantiomers have identical physical and chemical properties except for:
- Ability to rotate plane polarized light
- Chemical reactions with other molecules containing a stereogenic center

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Description

Test your knowledge on prodrugs, their applications, and core pharmacology concepts such as pharmacokinetics and pharmacodynamics. This quiz also covers the phases of drug development, from discovery to clinical trials. Challenge yourself to understand the principles behind drug design and evaluation.