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Questions and Answers
What is a characteristic of enantiomers?
What is a characteristic of enantiomers?
What defines structural isomers?
What defines structural isomers?
What does partial antagonism imply?
What does partial antagonism imply?
Which statement describes chemical antagonism?
Which statement describes chemical antagonism?
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What is a racemic mixture?
What is a racemic mixture?
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What does a positive LogP value indicate about a compound's distribution?
What does a positive LogP value indicate about a compound's distribution?
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Which process does not require energy for drug movement across cell membranes?
Which process does not require energy for drug movement across cell membranes?
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What is the purpose of altering solubility in drug development?
What is the purpose of altering solubility in drug development?
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What is Fick's law of diffusion primarily concerned with?
What is Fick's law of diffusion primarily concerned with?
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How does the ionization of weak acids and bases affect drug absorption?
How does the ionization of weak acids and bases affect drug absorption?
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In the drug development process, what primarily occurs during the 'discovery' phase?
In the drug development process, what primarily occurs during the 'discovery' phase?
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What is one key factor that complicates drug development due to funding?
What is one key factor that complicates drug development due to funding?
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What role do special carriers play in drug movement across cell membranes?
What role do special carriers play in drug movement across cell membranes?
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What does a LogP value of 0 indicate about a compound's partitioning between two phases?
What does a LogP value of 0 indicate about a compound's partitioning between two phases?
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Which of the following drugs is derived from natural sources?
Which of the following drugs is derived from natural sources?
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What is a primary feature of passive (simple) diffusion?
What is a primary feature of passive (simple) diffusion?
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What is one of the primary reasons for regulatory approval of pharmaceuticals?
What is one of the primary reasons for regulatory approval of pharmaceuticals?
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What is the significance of Lipinski's Rule of 5 in drug development?
What is the significance of Lipinski's Rule of 5 in drug development?
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What can be inferred about drugs that are weak acids or bases in relation to tissue pH?
What can be inferred about drugs that are weak acids or bases in relation to tissue pH?
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Which of the following is true about the rabies vaccine developed by Louis Pasteur?
Which of the following is true about the rabies vaccine developed by Louis Pasteur?
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What challenge do companies face concerning patenting in drug development?
What challenge do companies face concerning patenting in drug development?
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What was one of the first controlled clinical trials conducted, and what substance was tested?
What was one of the first controlled clinical trials conducted, and what substance was tested?
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What factor influences the slow release of active agents in drug formulations?
What factor influences the slow release of active agents in drug formulations?
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What happens to the selectivity of a drug as its concentration increases?
What happens to the selectivity of a drug as its concentration increases?
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Which term best describes the ability of a drug to bind to its target?
Which term best describes the ability of a drug to bind to its target?
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What is the intrinsic efficacy of a full agonist?
What is the intrinsic efficacy of a full agonist?
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How do enzymes increase the rate of chemical reactions?
How do enzymes increase the rate of chemical reactions?
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What defines the potency of a drug?
What defines the potency of a drug?
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Which of the following best describes the role of the active site in enzymes?
Which of the following best describes the role of the active site in enzymes?
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What is the effect of an allosteric modulator on a receptor?
What is the effect of an allosteric modulator on a receptor?
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What is indicated by the IC50 value of a drug?
What is indicated by the IC50 value of a drug?
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Which type of binding occurs at the orthosteric site of a receptor?
Which type of binding occurs at the orthosteric site of a receptor?
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Which mechanism explains how enzymes lower activation energy?
Which mechanism explains how enzymes lower activation energy?
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Which component is NOT part of the cytochrome P450 system?
Which component is NOT part of the cytochrome P450 system?
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What is the primary function of glucuronidation in drug metabolism?
What is the primary function of glucuronidation in drug metabolism?
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What role does glutathione play in drug metabolism?
What role does glutathione play in drug metabolism?
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Which statement about codeine metabolism is correct?
Which statement about codeine metabolism is correct?
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What happens during paracetamol overdose?
What happens during paracetamol overdose?
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How are inactive prodrugs activated in the body?
How are inactive prodrugs activated in the body?
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Which of the following statements regarding drug elimination is false?
Which of the following statements regarding drug elimination is false?
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What is a key characteristic of phase II metabolic reactions?
What is a key characteristic of phase II metabolic reactions?
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Which drug is primarily converted by CYP2D6 into an active metabolite?
Which drug is primarily converted by CYP2D6 into an active metabolite?
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Which enzyme is primarily responsible for catalyzing glucuronidation?
Which enzyme is primarily responsible for catalyzing glucuronidation?
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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 = Log
10Partition 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.