Foundations of Drug Interaction Exam 1 Flashcards
What are the 3 phases of drug design?
Discovery, Optimization and Development
Define lead compound
A lead compound is a pharmacologically active agent that may still require modification for specific target.
Name the biochemical classes of targets for drugs from most popular to least
Enzymes (47%), G-protein coupled receptors (30%), Nuclear hormone receptors and transporters (8%), Ion channels (7%), Other receptors (4%), Miscellaneous (2%), DNA (1%), Integrins or Integral membrane proteins (1%)
Define Bioassay
A test using a live animal or plant (in vivo) or tissue (in vitro) to determine the biological activity of a substance, hormone, or drug
What are the general types of bioassays?
Assays using the whole organism (can be unicellular or multicellular) - Mechanism independent and non-selective
Assays using mammalian cell cultures such as cancer cell lines - mechanism independent but can indicate selectivity within a variety of cell lines
Assays using purified enzymes or receptors (cell free) - mechanism dependent and highly selective for specific protein target used
Assays using engineered microorganisms (cell based) - mechanism dependent and have a higher likelihood of being active in a pharmacological model
What types of samples can be used following the identification of a suitable bioassay?
Natural product compounds and synthetic compounds
What types of natural product compounds can be used? What is necessary when using a natural product compound?
Crude extracts - limited appeal for HTS
Pure compounds - offer great range of structural diversity
Deconvolution - separation of the active principle from inactive components
Dereplication - identification of previously identified bioactive compounds
What types of synthetic compound techniques are employed?
Combinatorial libraries:
- Less structural diversity than natural products
- Focus on specific structure types for lead optimization
- Thousands to Millions of compounds
Virtual Libraries:
- used if structure of target is known
- compounds with high affinity are then screened in lab using appropriate bioassay
- composed of mostly synthetic compounds
Desired characteristics to keep in mind during lead compound optimization
Selectivity, potency, absorption, metabolism, low toxicity, duration of action, ADME
Examples of SAR studies
Structure-Activity Relationships:
- Chain branching and homologation
- Ring transformation
- Classical and non-classical bioisosteric replacements
What is CADD and what types are there?
Computer Assisted Drug Design - used SAR and QSAR to narrow the number of compounds to be tested in assays
Molecular modeling and structure based drug design
Define Lipinski’s Rule of 5
A set of rules that help medicinal chemists decide which compounds have the highest likelihood of becoming a drug
- A molecular weight under n500
- Fewer than 10 hydrogen bond acceptors
- Fewer than 5 hydrogen bond donors
- A C log P value of less than 5 and greater than .5
Define pharmacophore
The three dimensional arrangement of the essential functional groups necessary to cause a biological response (the minimum structural features necessary for activity)
What is QSAR?
The use of math models to predict activity in untested compounds or define the structural features required for a good fit between the drug molecule and receptor
Log P
A measure of how well a compound will dissolve in water as opposed to lipid
C Log P
Also called calculated log p
Does not take into account ionization forms of the drug molecule at different pHs
What is homologation?
Involves the elongation of a saturated carbon chain
Define Isosteres
Molecules or ions with the same number of atoms and/OR the same number and arrangement of valence electrons
Define classical bioisosteres
Groups of atoms that have chemical and physical similarities producing broadly similar biological properties; steric, electronic, and solubility characteristics make them interchangeable in drugs of the same pharmacological class
Define nonclassical bioisosteres
Molecules or ions that share similar shapes, volumes, electronic distribution and physiochemical properties that together produce similar biological effects, but their structures do no follow an easily definable set of rules as above for classical isosteres. Steric size may be significantly different.
What are eutomers and distomers?
Eutomer is the stereoisomer with higher receptor affinity or activity, while a distomer has lower.
Name the different types of bonding interactions by decreasing strength.
Covalent, Ionic, Hydrogen, Ion-dipole, dipole-dipole, Hydrophobic (Van der Waals)
How is Log P calculated
Log (Concentration of drug in ocanol/concentration of drug in water)
What does the Log P represent?
A log P greater than 0.5 is insoluble; less than 0.5 is soluble in water
Summarize an ideal drug
Must be transported by the body fluids, traverse biological membrane barriers, escape widespread distribution, endure metabolic attack, penetrate in adequate concentration at the sites of action, interact in specific fashion causing an alteration of cellular function
What is the “first pass effect” and how is it avoided?
Movement of a drug through the gut, into the portal vein, and into the liver for metabolism.
Sublingual avoids the first pass effect, rectal partially avoids and parenteral entirely avoids, leading to 100 percent absorption
What are some barriers to ADME?
Biological membranes including several layers of cell-skin, single layer of cells-skin, and cell membranes
Physical barriers include characteristics of the drug, formulation and protein binding in the blood stream
Define bioavailability
The rate and extent to which an active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of action (mostly used as a parameter for intact drug that reaches the systemic circulation)
Define Bioequivalence
The comparison of bioavailabilities of different formulations, drug products, or batches of the same drug product
What are the two main types of transport across a cell membrane?
Paracellular which involves changing how two cells are connected or the use of a path in between adjacent cells
Transcellular which is the most widely used
Types of transcellular transport and which follow Frick’s Law of Diffusion?
Endocytosis, Active, Facilitated and Passive
Active and facilitated only follow Frick’s Law of Diffusion at low concentrations but Passive follows Frick’s Law
Name some examples of small polar molecule-s that are able to pass through membranes
Water, glycerol, urea and ethanol
Name the two common membrane transport families
Solute Carrier Superfamily (SLC) and the ATP binding cassette superfamily (ABC)
ABC includes P-glycoprotein and are largely expressed on cell surface
Describe PepT1
Member of SLC superfamily
ACE inhibitors are a common substrate for these channels
Proton depended for transport of di and tripeptides
Describe P-Glycoprotein
- Also called multi-drug resistance protein (MDR1)
- Effluxes out man antineoplastic drugs
- Large expression in gut and blood brain barrier as well as other locations such as the small intestines, kidney, liver bile ducts, ovaries and placenta
- Always expressed in cancers
- Expressed on basolateral, or lumen side of the brain
What is the effect of rifampin on digoxin
Causes overexpression of PGP, leading to a decrease in digoxin levels
Name the organs of digestion and their purpose(s).
- Oral cavity, teeth, and tongue
- Salivary glands - enzymes break down carbs
- Pharynx - propel material to esophagus by pharyngeal muscles
- Esophagus - transport materials to stomach
- Stomach - chemical and mechanical breakdown
- Liver - secretion of bile for lipid digestion and storage of nutrients
- Gallbladder - storage of concentration of bile
- Pancreas - exocrine cells that secrete buffers and digestive enzymes; endocrine cells secrete hormones
- Small intestine - enzymatic digestion and absorption of water, organic substrates, vitamins and ions
- Large intestine - dehydration and compaction
General functions of Digestive Tract
Ingestion, mechanical processing, digestion, secretion, absorption, compaction
pH levels in the GI
Small intestine: Duodenum, Jejunum (5.7-6.4)
Stomach (1-2)
Small Intestine: Ileum (7.3-7.7)
Large Intestine (5.7-6.8)
List factors that influence bioavailability of oral drugs
Drug substance physiochemical properties (lipid or water solubility, pH and pKa), Pharmaceutical ingredients (fillers, binders, coatings, disintegrative agents, lubricants, suspending agents, flavoring and coloring agents, preservatives and stabilizing agents), Dosage form characteristics (disintegration rate, dissolution time of drug in dosage form, product age and storage conditions), Physiological factors and patient characteristics (gastric emptying time, gastrointestinal abnormality or pathological condition, gastric contents, other drugs or food, fluids, GI pH), and Drug Metabolism
What is it called when a drug is sent from the liver back to the GI tract?
Enterohepatic circulation
What is the portal triad?
Formed of a branch from the bile duct, hepatic portal vein and hepatic portal artery
What are different options for getting a drug through the epidermis?
Subcutaneous, intramuscular, intravenous, transdermal, and implantation
What are the layers of the epidermis and which is the most difficult to cross?
Stratum corneum, stratum lucidum, stratum granulosm, stratum spinosm, stratum basale (stratum corneum most difficult)
Name three cells of the epidermis and their function
Melanocytes - melanin producing
Langerhans cells - antigen presenting immune cells
Merkel cells - sensory cells
What are the three main routes of skin absorption?
Intracellular, transappendageal using glands such as sebaceous/hair follicles and sweat ducts, and intercellular
What are good sites for topical absorption?
Palms, soles, lower back and inside upper arms
What variables differ between patients with regards to topical absorption?
Tissue thickness, lipid concentration, hydration, dequamation rate, hair and gland density, metabolism, age, gender, infections, burns and abrasions
What characteristics make it so hard for drugs to absorb across the blood brain barrier?
- Formation of tight junctions
- Low rate of endocytosis
- PGP expression
What characteristics describe distribution across the placental barrier?
- Some permeability of ions and essential vitamins
- PGP serves protective role as in the blood brain barrier
- Caffeine (along with some other drugs) has a high volume of distribution so pregnant women must monitor their consumption
Describe the volumes of the body
Plasma = 4 liters
Interstitial volume = 10 liters (together they are extracellular volume)
Intracellular volume = 28 liters
Total = 42 liters
What do the various volumes of distribution mean:
- More than 40
- Less than 40, such as 5
- 14 or 15
- 40
- drug is sitting in highly enriched compartments of muscle and fat
- stuck in plasma
- in interstitial fluid or extracellular space
- evenly distributed
What influences volume of distribution?
Water solubility, lipid solubility, tissue binding, blood flow, extent of drug protein binding in plasma or tissue
Name mediums of drug excretion
Urine, bile (major routes)
Sweat, expired air, breast milk or seminal fluid (minor routes)
What are the possible consequence of biotransformation?
Decrease in activity (detoxification), Increase in polarity, Increase in activity or bioactiviation (prodrug), Increase in activity (toxification)
What are the benefits of prodrugs?
Enhanced absorption, targeted-drug deliver-activation in specific site, improved distribution, formulation and administration, decrease in toxicity and decreased excretion
What are the two phases of metabolism?
Phase 1:
- Oxidation, hydrolysis, reductive
- this phase adds or exposes a functional group
Phase 2 - Conjugative
- increases the size or hydrophilicity of drug molecules
- faster than phase 1 but require cofactors
- reactions include methylation, acetylation, sulfate conjugation, glucuronide conjugation, glutathione conjugation, and amino acid conjugation
Describe the most studies enzyme in phase 1 metabolism
Cytochrome P450
- responsible for oxidation and reduction
- found in ER and traces in mitochondria
- contains HEME
- Utilizes NADPH and molecular oxygen in ER
- Mitochondria electron transfer occurs via redoxin reductase
Describe grapefruit inhibition
Inhibits CYP3A4
- increases felodipine oral availability in humans by decreasing CYP3A4 protein expression
- inhibits excretory enzymes leading to drug buildup in the body
