Week 1 Flashcards
Appreciate how drugs selectively interact with their biological targets
Key aspects to appreciate:
1) Molecular Structure and Specificity:
// Drugs are designed with specific molecular structures that allow them to interact selectively with particular biological targets, such as proteins or enzymes.
//The three-dimensional shape and chemical properties of a drug determine its ability to bind to a target with high specificity.
2) Lock-and-Key Model:
The interaction between drugs and their targets is often likened to a lock-and-key model. The drug (key) fits into the target’s binding site (lock) with precision.
Complementary shapes and chemical properties ensure a specific and snug fit, enabling effective interaction.
3) Binding Affinity:
The strength of interaction between a drug and its target is termed binding affinity. Higher affinity leads to a more stable and long-lasting interaction.
Drug design aims to optimize binding affinity to enhance therapeutic effectiveness.
4) Target Diversity:
Biological targets are diverse, including receptors, enzymes, ion channels, and nucleic acids. Each target plays a specific role in cellular processes.
Drugs are tailored to interact selectively with a particular target relevant to the disease or condition being treated.
5) Functional Consequences:
Drug binding to a biological target induces specific functional consequences. For example, a drug may inhibit or enhance the activity of an enzyme, block a receptor, or modulate a signaling pathway.
These functional changes contribute to the therapeutic effects of the drug.
Rationalise ionisation (pKa) and lipophilicity (logP/D) of small molecule drug structures, and how these impact on solubility and permeability
The ionization constant (pKa) and lipophilicity (expressed as logP or logD) are crucial
physicochemical properties of small molecule drug structures, influencing their solubility and permeability. Here’s a rationalization of how these factors interplay:
1) pKa (Ionization Constant):
Definition: pKa represents the pH at which 50% of a drug is ionized and 50% is unionized. It reflects the acidity or basicity of a compound.
Impact on Solubility: Ionization significantly influences a drug’s solubility. Ionized forms are often more water-soluble than their non-ionized counterparts.
Impact on Permeability: Ionization affects a drug’s ability to permeate biological membranes. Unionized (non-polar) forms generally have higher membrane permeability.
2) Lipophilicity (logP/D):
Definition: Lipophilicity, expressed as logP (partition coefficient between n-octanol and water) or logD (distribution coefficient accounting for ionization), measures a drug’s affinity for lipid-rich environments.
Impact on Solubility: Lipophilicity influences a drug’s solubility in nonpolar solvents. Increased lipophilicity may reduce water solubility.
Impact on Permeability: Lipophilicity plays a crucial role in membrane permeability. Moderately lipophilic compounds often have optimal permeability, balancing their affinity for both water and lipid environments.
3) Interplay and Optimization:
Optimal Lipophilicity: While lipophilicity can enhance membrane permeability, excessively lipophilic compounds may suffer from poor aqueous solubility, potentially limiting bioavailability. Balancing lipophilicity is key.
pKa and Ionization State: The ionization state at physiological pH impacts both solubility and permeability. Compounds with a pKa near physiological pH can exist in a balance of ionized and unionized forms, maximizing solubility and permeability.
4) Applications in Drug Design:
Structure-Activity Relationships (SAR): Medicinal chemists use SAR to optimize pKa and lipophilicity, aiming for compounds with desirable solubility and permeability profiles.
Prodrug Design: Manipulating pKa and lipophilicity through prodrug design can enhance absorption, as prodrugs may undergo bioconversion to more favorable forms in vivo.
Understand drug stability, with respect to chemical hydrolysis and free radical
oxidation, and how these impacts on formulation and medicine use
Drug Stability:
Drug stability refers to the ability of a pharmaceutical formulation to maintain its chemical, physical, and therapeutic properties over time. Two significant processes that can impact drug stability are chemical hydrolysis and free radical oxidation.
1) Chemical Hydrolysis:
Definition: Chemical hydrolysis involves the cleavage of chemical bonds in a drug molecule due to the presence of water, resulting in the formation of new compounds.
Impact on Stability: Hydrolysis can lead to degradation of the drug, reducing its potency and efficacy.
Formulation Considerations:
Buffering: Formulations may include buffer systems to maintain a stable pH, minimizing the impact of acidic or basic hydrolysis.
Water Content: Controlling the water content in formulations is crucial to prevent excessive hydrolysis.
Prodrug Design: Prodrugs, which are inactive forms of a drug converted to the active form in vivo, may be designed to mitigate susceptibility to hydrolysis.
2) Free Radical Oxidation:
Definition: Free radical oxidation involves the reaction of drugs with reactive oxygen species (ROS), leading to the formation of free radicals and oxidative degradation.
Impact on Stability: Oxidation can result in the loss of drug efficacy and the
formation of toxic byproducts.
Formulation Considerations:
Antioxidants: Formulations often include antioxidants to scavenge free radicals and protect the drug from oxidative degradation.
Packaging: Proper packaging, such as using light-resistant containers, can prevent drug exposure to light, which may induce free radical oxidation.
Inert Gases: Inert gases, such as nitrogen, may be used to displace oxygen in packaging, reducing the likelihood of oxidation.
Impacts on Formulation and Medicine Use:
Shelf Life: Understanding and mitigating chemical hydrolysis and oxidation are essential for determining a drug’s shelf life.
Storage Conditions: Recommendations for storage conditions, such as temperature and humidity, are formulated to minimize the impact of these degradation processes.
Patient Compliance: Degraded drugs may not only be less effective but also potentially harmful. Ensuring stability is crucial for maintaining patient safety and compliance
Understand the mechanism of action of antimicrobial agents and be able to give examples
1) Cell Wall Inhibition:
Mechanism: Antimicrobial agents disrupt the synthesis or integrity of bacterial cell walls, leading to cell lysis.
Example: Penicillins (e.g., amoxicillin) inhibit bacterial cell wall synthesis by targeting enzymes involved in peptidoglycan formation.
2) Cell Membrane Disruption:
Mechanism: Antimicrobial agents alter the integrity of bacterial cell membranes, causing leakage of cellular contents.
Example: Polymyxins (e.g., polymyxin B) disrupt bacterial cell membranes, particularly in Gram-negative bacteria.
3) Protein Synthesis Inhibition (Translation):
Mechanism: Antimicrobial agents interfere with bacterial protein synthesis by targeting the ribosome.
Example: Aminoglycosides (e.g., gentamicin) bind to bacterial ribosomes, disrupting protein synthesis and causing mistranslation.
4) Nucleic Acid Synthesis Inhibition:
Mechanism: Antimicrobial agents interfere with the synthesis of bacterial DNA or RNA.
Example: Fluoroquinolones (e.g., ciprofloxacin) inhibit bacterial DNA gyrase, preventing DNA replication.
5) Metabolic Pathway Disruption:
Mechanism: Antimicrobial agents disrupt essential metabolic pathways in bacteria.
Example: Sulfonamides (e.g., sulfamethoxazole) inhibit folic acid synthesis, a crucial step in bacterial metabolism.
6) Anti-folate Activity:
Mechanism: Antimicrobial agents interfere with the utilization of folate, a necessary cofactor for nucleic acid synthesis.
Example: Trimethoprim inhibits bacterial dihydrofolate reductase, disrupting folate metabolism.
7) Antimetabolite Activity:
Mechanism: Antimicrobial agents mimic essential metabolites, disrupting cellular processes.
Example: Isoniazid interferes with mycolic acid synthesis in Mycobacterium tuberculosis
Understand what is meant by selective toxicity in terms of infection management
Selective toxicity, in the context of infection management, refers to the ability of an antimicrobial agent to specifically target and harm pathogenic microorganisms while minimizing damage to host cells. The goal is to eradicate or inhibit the growth of infectious agents without causing significant harm to the patient. Achieving selective toxicity is a fundamental principle in the design and use of antimicrobial agents for effective infection management. Several key aspects contribute to selective toxicity:
1) Target-Specific Mechanisms:
Antimicrobial agents should have mechanisms of action that selectively interfere with processes unique to the microbial pathogens, such as cell wall synthesis, protein synthesis, or nucleic acid replication.
2) Differences in Cellular Structures:
Exploiting structural and functional differences between microbial cells and host cells allows for the development of agents that specifically target the pathogens.
For example, antibiotics targeting bacterial cell walls exploit differences in the structure of bacterial and mammalian cell walls.
3) Unique Metabolic Pathways:
Targeting microbial-specific metabolic pathways, enzymes, or proteins allows for selective toxicity. Inhibition of these pathways disrupts essential processes in the microorganism without affecting host cells.
4) Specific Drug-Pathogen Interactions:
Antimicrobial agents should have a higher affinity for microbial targets compared to host cell targets, ensuring preferential binding and activity against the pathogens.
5) Limited Cross-Resistance:
Ideally, selective toxicity is associated with a limited potential for the development of cross-resistance between antimicrobial agents, reducing the risk of resistance spreading from one microorganism to another.
Examples of Selectively Toxic Antimicrobial Agents:
1) Penicillins:
Selective toxicity is achieved by targeting bacterial cell wall synthesis through the inhibition of enzymes like transpeptidases, which are specific to bacteria.
2) Fluconazole (Antifungal):
Targets the synthesis of ergosterol, a fungal-specific component of the cell membrane, achieving selective toxicity against fungi.
Define a cell and describe the structure and function of the major organelles
A cell is the basic structural and functional unit of life. It is the smallest unit of an organism that can carry out all the necessary functions for life, including metabolism, reproduction, and response to the environment. Cells can be categorized into two main types: prokaryotic cells, lacking a true nucleus and membrane-bound organelles, and eukaryotic cells, which have a nucleus and membrane-bound organelles.
Eukaryotic Cell Structure and Function of Major Organelles:
1) Cell Membrane (Plasma Membrane):
Structure: The outer boundary of the cell, composed of a phospholipid bilayer embedded with proteins.
Function: Regulates the passage of substances into and out of the cell, maintaining cellular integrity and selectively permeable.
2) Nucleus:
Structure: Surrounded by a nuclear envelope, contains chromatin (DNA and proteins) and a nucleolus.
Function: Controls cellular activities by directing protein synthesis and housing genetic material.
3) Endoplasmic Reticulum (ER):
Structure: Network of membranous tubules and sacs.
Function: Rough ER, studded with ribosomes, is involved in protein synthesis and modification. Smooth ER is involved in lipid synthesis, detoxification, and calcium storage.
4) Ribosomes:
Structure: Small, non-membranous particles composed of RNA and protein.
Function: Site of protein synthesis where mRNA is translated into polypeptide chains.
5) Golgi Apparatus (Golgi Complex):
Structure: Stack of flattened membranous sacs.
Function: Modifies, sorts, and packages proteins and lipids for secretion or delivery to other cellular locations.
6) Mitochondria:
Structure: Double-membraned organelles with inner folds (cristae).
Function: Site of cellular respiration, producing ATP through the oxidation of glucose.
7) Lysosomes:
Structure: Membrane-bound sacs containing digestive enzymes.
Function: Breaks down cellular waste, foreign materials, and damaged organelles through intracellular digestion.
8) Vacuoles:
Structure: Membrane-bound sacs.
Function: Storage of nutrients, waste products, and pigments; maintenance of turgor pressure in plant cells.
9)Cytoskeleton:
Structure: Network of protein filaments (microtubules, microfilaments, and intermediate filaments).
Function: Provides structural support, facilitates cell movement, and helps maintain cell shape.
Describe the main routes of administration and dosage types of medicines
Routes of Administration:
1) Oral Administration:
Description: Medication is taken through the mouth and swallowed.
Advantages: Convenient, non-invasive, and suitable for a wide range of drugs.
Disadvantages: Absorption may be variable; affected by factors like food and gastric emptying.
2) Topical Administration:
Description: Medication is applied directly to the skin or mucous membranes.
Advantages: Localized effect, avoids systemic side effects.
Disadvantages: Limited to certain types of drugs; absorption may vary.
3) Inhalation:
Description: Medication is delivered to the respiratory system through inhalation.
Advantages: Rapid absorption, effective for respiratory conditions.
Disadvantages: Limited to respiratory medications.
4) Intravenous (IV) Administration:
Description: Medication is directly injected into a vein.
Advantages: Rapid and precise drug delivery, suitable for emergencies.
Disadvantages: Invasive, requires skill, and poses infection risks.
5) Intramuscular (IM) Administration:
Description: Medication is injected into a muscle.
Advantages: Allows for sustained release formulations.
Disadvantages: Requires injection; absorption rate may vary.
6) Subcutaneous (SC) Administration:
Description: Medication is injected into the subcutaneous tissue.
Advantages: Suitable for slow-release formulations.
Disadvantages: Requires injection; absorption rate may vary.
7) Rectal Administration:
Description: Medication is inserted into the rectum.
Advantages: Useful when oral administration is not feasible.
Disadvantages: Variable absorption; may be uncomfortable.
8) Transdermal Administration:
Description: Medication is delivered through a patch applied to the skin.
Advantages: Continuous drug release, avoids first-pass metabolism.
Disadvantages: Limited to certain drugs; slow onset of action.
Dosage Forms:
1) Tablets and Capsules:
Description: Solid forms containing a specific dose of medication.
Advantages: Convenient, precise dosing.
Disadvantages: May have slower onset compared to liquids.
2) Liquid Formulations:
Description: Solutions, suspensions, or syrups containing the medication in liquid form.
Advantages: Rapid onset of action, suitable for patients unable to swallow solid forms.
Disadvantages: Stability issues, may require refrigeration.
3) Injections:
Description: Medication is delivered using a syringe and needle.
Advantages: Rapid onset, precise dosing.
Disadvantages: Invasive, requires skill, and poses infection risks.
4) Topical Formulations:
Description: Creams, ointments, or patches applied to the skin.
Advantages: Localized effect, avoids systemic side effects.
Disadvantages: Limited to certain types of drugs; absorption may vary.
5)Inhalers and Nebulizers:
Description: Medication is delivered directly to the respiratory system.
Advantages: Effective for respiratory conditions, rapid onset.
Disadvantages: Limited to respiratory medications.
6) Suppositories:
Description: Solid dosage forms inserted into the rectum or vagina.
Advantages: Useful when oral administration is not feasible.
Disadvantages: Variable absorption; may be uncomfortable.
Q2) Describe in detail the stepwise process involved in folding a primary polypeptide sequence into fully functional three-dimensional globular protein structure. In your answer mention all the forces which confer structural stability, taking into account the role of aqueous environment and also give some examples of typical amino acids involved in each such case.
What are proteins made of?
Building blocks of proteins are amino acids. Compose of an amino group, a carboxyl group, a hydrogen atom and a side chain. Multiple amino acids are linked together by peptide bonds. The linear sequence of amino acids within a protein is considered the primary structure. 20 amino acids in total
Primary structure
Linear sequence of amino acids→ linked by peptide bonds. Determined by genetic code. Have aside chains (R groups) that vary in size, charge and chemical properties
Secondary structure
Alpha helices
Alanine, leucine and glutamic acid have strong propensity to form α helices. In a α helices the polypeptide chain forms a right-handed spiral
Beta sheets
Glycine and proline might contribute to the formation of beta sheets .The polypetide chain adopts a zigzag pattern and hydrogen bonds form between adjacent strands
Tertiary Structure
Hydrophobic interactions
Hydrophobic amino acids (valine, isoleucine, phenylalanine). Tend to cluster together to minimize exposure to aqueous environment. Hydrophobic core contributes to the stability of the folded structure
Electrostatic interactions
Positively charged amino acids (lysine and arginine). Form ionic bonds with negatively charged amino acids (aspartic acid and glutamic acid). Stabilize the proteins tertiary structure
Disulfide bonds
Cysteine residues form covalent disulfide between sulfur atoms. These bonds cross link different parts of the polypeptide chain. Contribute to overall stability
Quaternary Structures
Consists of multiple polypeptide chains that come together to form functional protein complex. The interaction between these subunits such as hydrophobic interactions, hydrogen bonds and disulfide bonds play a crucial role in stabilizing the quartnary structure
Aqueous environment
Hydrogen bonds= Aqueous environments facilitate the formation of hydrogen bonds which are essential for stabilizing secondary and tertiary structures. These bonds involve the partial positive and negative charges of hydrogen and oxygen (present between carbonyl oxygen and amide hydrogen in alpha helices and beta sheets
Extra info: If protein misfolding occurs.Loss of function, Toxic function , disease, cellular stress and inflammation
definitions for agonist, partial agonist, inverse agonist, competitive antagonist, non-competitive agonist, negative allosteric modulator, positive allosteric modulator
Agonist= They activate the target, they have affinity(attracted to the target) and efficacy(cause response)
Partial agonist= they produce a response but not full response
Inverse agonist= produces the opposite effect of a natural ligand
Competitive antagonist= antagonist prevents agonists from binding to the receptor. A competitive one binds to the same site as an agonist
Non-competitive agonist= binds to different sites from agonist still preventing agonist binding
Negative allosteric modulator= binds to a different site on the receptor and decreases the affinity and efficacy of the drug that binds to the main site
Positive allosteric modulator= binds to a different site on the receptor but it increases the affinity and efficacy of the drug binding to the main site
Definition for activator, inducer,competitive inhibitor, non-competitive inhibitor
At enzyme
activator
molecules that bind to enzymes and increase their catalytic activity.
Enzyme activators must be allosteric
must allow the substrate to bind to the enzyme for the reaction to occur
inducer
a type of drug that increases the metabolic activity of an enzyme
either by binding to the enzyme and activating it, or by increasing the expression of the gene coding for the enzyme
This results in a decrease in the effect of certain other drugs
Competitive inhibitor
A substrate molecule is prevented from binding to the active site of an enzyme by a molecule that is very similar in structure to the substrate.
compete with the substrate for the active site.
Non-competitive inhibitor
Noncompetitive inhibition occurs when an inhibitor binds to the enzyme at a site other than the active site,
known as the allosteric site resulting in decreased efficacy of the enzyme.
The inhibitor, which is not a substrate, changes the overall shape of the site for the normal substrate so that it does not fit as well as before, which slows or prevents the reaction from taking place.
Briefly discuss what a eukaryotic cell is and what a prokaryotic cell is. List FOUR physiological differences between eukaryotic and prokaryotic cells.
Nucleus: Membrane-bound nucleus that contains cells genetic material
Nucleoid: lacks a true membrane-bound nucleus. Instead, genetic material located in nucleoids not enclosed by a nuclear membrane
**
Membrane-bound organelle: contains endoplasmic reticulum, mitochondria, golgi apparatus, lysosomes **
No membrane-bound organelle: may have specialised structures such as ribosomes and flagella but they are not enclosed in membranes
**Size: generally larger and more complex **
Size: typically smaller and simpler
**Cell division: undergo mitosis( complex process of cell division, produces genetically identical daughter cells **
Cell division: divide through binary fission, a simple form of cell division where a cell replicates its DNA and splits into two identical daughter cells
**Cytoskeleton: made up of protein filaments, produce structural support
**
Cytoskeleton: less complex than eukaryotic cells
**multicellularity **
Unicellularity:
**Examples: animal, plants, fungi, protist cells **
Examples: bacteria, archaea cells
bold= eukaryotic cells
B) When considering antimicrobials, briefly explain what is meant by selective toxicity.
Selective toxicity= refers to the ability of these substances to specifically target and harm the microorganism causing an infection
A selectively toxic microbial should kill or inhibit the growth of bacteria, viruses, and fungi while sparing host cells and tissues
E.g. antibiotics may target bacteria cell walls which are absent in human cells to disrupt bacterial cell structure
c)Briefly describe what is meant be the terms bacteriostatic and bactericidal and give an example of an antibiotic within each category.
Bacteriostatic
Bactericidal
Definition:
inhibit the growth and reproduction of bacteria
not necessarily kill them
Temporarily stops bacteria from multiplying
Allows hosts immune system to eliminate existing bacteria
Example: Tetracycline
Works by preventing bacterial ribosomes from synthezing proteins
Halts bacterial replication and allows the host immune system to eliminate bacteria
Bacterialcidal
Definition:
Actively kills bacteria
Directly target and destroy bacterial cells leading to their death
Example: penicillin
Interferes with the synthesis of bacterial cell walls
Causes walls to weaken and rupture
Leads to death of the bacteria due to loss of structural integrity
D) What is the rationale for prescribing co-amoxicalv to HF in the above scenario? Include in your answer an overview of the mode of action for this drug.
Sometimes amoxicillin cannot kill the bacteria on its own
Some bacteria types of bacteria produce an enzyme called beta-lactamas that breaks down amoxicillin
Co-amoxiclav combines amoxicillin with claulanic acid to kill the bacteria that is causing infection
Clavulanic acid revents the enzyme doing that so amoxicillin can work property to kill bacteria
Q5) One of the medicines you will have learnt about previously is omeprazole
Omeprazole
Proton pump inhibitor
Works by reducing the production of stomach acid
Taken before a meal
