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Pharmacy School 2015-16 > Foundations of Drug Interaction Exam 1 > Flashcards

Foundations of Drug Interaction Exam 1 Flashcards

1
Q

What are the 3 phases of drug design?

A

Discovery, Optimization and Development

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2
Q

Define lead compound

A

A lead compound is a pharmacologically active agent that may still require modification for specific target.

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3
Q

Name the biochemical classes of targets for drugs from most popular to least

A

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%)

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4
Q

Define Bioassay

A

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

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5
Q

What are the general types of bioassays?

A

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

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6
Q

What types of samples can be used following the identification of a suitable bioassay?

A

Natural product compounds and synthetic compounds

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7
Q

What types of natural product compounds can be used? What is necessary when using a natural product compound?

A

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

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8
Q

What types of synthetic compound techniques are employed?

A

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
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9
Q

Desired characteristics to keep in mind during lead compound optimization

A

Selectivity, potency, absorption, metabolism, low toxicity, duration of action, ADME

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10
Q

Examples of SAR studies

A

Structure-Activity Relationships:

  1. Chain branching and homologation
  2. Ring transformation
  3. Classical and non-classical bioisosteric replacements
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11
Q

What is CADD and what types are there?

A

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

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12
Q

Define Lipinski’s Rule of 5

A

A set of rules that help medicinal chemists decide which compounds have the highest likelihood of becoming a drug

  1. A molecular weight under n500
  2. Fewer than 10 hydrogen bond acceptors
  3. Fewer than 5 hydrogen bond donors
  4. A C log P value of less than 5 and greater than .5
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13
Q

Define pharmacophore

A

The three dimensional arrangement of the essential functional groups necessary to cause a biological response (the minimum structural features necessary for activity)

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14
Q

What is QSAR?

A

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

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15
Q

Log P

A

A measure of how well a compound will dissolve in water as opposed to lipid

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16
Q

C Log P

A

Also called calculated log p

Does not take into account ionization forms of the drug molecule at different pHs

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17
Q

What is homologation?

A

Involves the elongation of a saturated carbon chain

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18
Q

Define Isosteres

A

Molecules or ions with the same number of atoms and/OR the same number and arrangement of valence electrons

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19
Q

Define classical bioisosteres

A

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

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20
Q

Define nonclassical bioisosteres

A

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.

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21
Q

What are eutomers and distomers?

A

Eutomer is the stereoisomer with higher receptor affinity or activity, while a distomer has lower.

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22
Q

Name the different types of bonding interactions by decreasing strength.

A

Covalent, Ionic, Hydrogen, Ion-dipole, dipole-dipole, Hydrophobic (Van der Waals)

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23
Q

How is Log P calculated

A

Log (Concentration of drug in ocanol/concentration of drug in water)

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24
Q

What does the Log P represent?

A

A log P greater than 0.5 is insoluble; less than 0.5 is soluble in water

25
Q

Summarize an ideal drug

A

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

26
Q

What is the “first pass effect” and how is it avoided?

A

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

27
Q

What are some barriers to ADME?

A

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

28
Q

Define bioavailability

A

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)

29
Q

Define Bioequivalence

A

The comparison of bioavailabilities of different formulations, drug products, or batches of the same drug product

30
Q

What are the two main types of transport across a cell membrane?

A

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

31
Q

Types of transcellular transport and which follow Frick’s Law of Diffusion?

A

Endocytosis, Active, Facilitated and Passive

Active and facilitated only follow Frick’s Law of Diffusion at low concentrations but Passive follows Frick’s Law

32
Q

Name some examples of small polar molecule-s that are able to pass through membranes

A

Water, glycerol, urea and ethanol

33
Q

Name the two common membrane transport families

A

Solute Carrier Superfamily (SLC) and the ATP binding cassette superfamily (ABC)

ABC includes P-glycoprotein and are largely expressed on cell surface

34
Q

Describe PepT1

A

Member of SLC superfamily
ACE inhibitors are a common substrate for these channels
Proton depended for transport of di and tripeptides

35
Q

Describe P-Glycoprotein

A
  • 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
36
Q

What is the effect of rifampin on digoxin

A

Causes overexpression of PGP, leading to a decrease in digoxin levels

37
Q

Name the organs of digestion and their purpose(s).

A
  1. Oral cavity, teeth, and tongue
  2. Salivary glands - enzymes break down carbs
  3. Pharynx - propel material to esophagus by pharyngeal muscles
  4. Esophagus - transport materials to stomach
  5. Stomach - chemical and mechanical breakdown
  6. Liver - secretion of bile for lipid digestion and storage of nutrients
  7. Gallbladder - storage of concentration of bile
  8. Pancreas - exocrine cells that secrete buffers and digestive enzymes; endocrine cells secrete hormones
  9. Small intestine - enzymatic digestion and absorption of water, organic substrates, vitamins and ions
  10. Large intestine - dehydration and compaction
38
Q

General functions of Digestive Tract

A

Ingestion, mechanical processing, digestion, secretion, absorption, compaction

39
Q

pH levels in the GI

A

Small intestine: Duodenum, Jejunum (5.7-6.4)
Stomach (1-2)
Small Intestine: Ileum (7.3-7.7)
Large Intestine (5.7-6.8)

40
Q

List factors that influence bioavailability of oral drugs

A

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

41
Q

What is it called when a drug is sent from the liver back to the GI tract?

A

Enterohepatic circulation

42
Q

What is the portal triad?

A

Formed of a branch from the bile duct, hepatic portal vein and hepatic portal artery

43
Q

What are different options for getting a drug through the epidermis?

A

Subcutaneous, intramuscular, intravenous, transdermal, and implantation

44
Q

What are the layers of the epidermis and which is the most difficult to cross?

A

Stratum corneum, stratum lucidum, stratum granulosm, stratum spinosm, stratum basale (stratum corneum most difficult)

45
Q

Name three cells of the epidermis and their function

A

Melanocytes - melanin producing
Langerhans cells - antigen presenting immune cells
Merkel cells - sensory cells

46
Q

What are the three main routes of skin absorption?

A

Intracellular, transappendageal using glands such as sebaceous/hair follicles and sweat ducts, and intercellular

47
Q

What are good sites for topical absorption?

A

Palms, soles, lower back and inside upper arms

48
Q

What variables differ between patients with regards to topical absorption?

A

Tissue thickness, lipid concentration, hydration, dequamation rate, hair and gland density, metabolism, age, gender, infections, burns and abrasions

49
Q

What characteristics make it so hard for drugs to absorb across the blood brain barrier?

A
  1. Formation of tight junctions
  2. Low rate of endocytosis
  3. PGP expression
50
Q

What characteristics describe distribution across the placental barrier?

A
  1. Some permeability of ions and essential vitamins
  2. PGP serves protective role as in the blood brain barrier
  3. Caffeine (along with some other drugs) has a high volume of distribution so pregnant women must monitor their consumption
51
Q

Describe the volumes of the body

A

Plasma = 4 liters
Interstitial volume = 10 liters (together they are extracellular volume)

Intracellular volume = 28 liters

Total = 42 liters

52
Q

What do the various volumes of distribution mean:

  1. More than 40
  2. Less than 40, such as 5
  3. 14 or 15
  4. 40
A
  1. drug is sitting in highly enriched compartments of muscle and fat
  2. stuck in plasma
  3. in interstitial fluid or extracellular space
  4. evenly distributed
53
Q

What influences volume of distribution?

A

Water solubility, lipid solubility, tissue binding, blood flow, extent of drug protein binding in plasma or tissue

54
Q

Name mediums of drug excretion

A

Urine, bile (major routes)

Sweat, expired air, breast milk or seminal fluid (minor routes)

55
Q

What are the possible consequence of biotransformation?

A

Decrease in activity (detoxification), Increase in polarity, Increase in activity or bioactiviation (prodrug), Increase in activity (toxification)

56
Q

What are the benefits of prodrugs?

A

Enhanced absorption, targeted-drug deliver-activation in specific site, improved distribution, formulation and administration, decrease in toxicity and decreased excretion

57
Q

What are the two phases of metabolism?

A

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
58
Q

Describe the most studies enzyme in phase 1 metabolism

A

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
59
Q

Describe grapefruit inhibition

A

Inhibits CYP3A4

  • increases felodipine oral availability in humans by decreasing CYP3A4 protein expression
  • inhibits excretory enzymes leading to drug buildup in the body

Pharmacy School 2015-16 (34 decks)

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