lecture 1 of organisms and chemicals

Question 1

what is a substance and what is it interchangeable for

Answer 1

substance = referring to chemical compound
interchangeable for xenobiotic, chemical, drug, toxin

Question 2

how can a body change a substance

Answer 2

body may change substance through metabolism
this may change the parent compound and/or the metabolite

Question 3

what is the difference between pharmacokinetics and pharmacodynamics

Answer 3

kinetics: how substance goes through the body
dynamics: the outcome of the substance

Question 4

what are the 3 factors to consider with route of exposure/administration

Answer 4

1. where in the body
2. how does it get there
3. what else does the substance encounter in the body

Question 5

how can concentration of the substance change in the body once absorbed

Answer 5

concentration of the substance goes from nothing or very low to increasing. once it is in the body, either it moves from the site of absorption to other parts or it doesn’t get distributed very far (like creams)

if it moves from the site of concentration -> it can be biotransformed, metabolized, or form other products

Question 6

what are the four steps of pharmacokinetics

Answer 6

1. absorption
2. distribution
3. metabolism
4. elimination

Question 7

define adme

Answer 7

they are the four fundamental principles that are applicable to all xenobiotics and organisms

Question 8

define pharmacokinetics and bioavailability, what is their relationship

Answer 8

pharm: how the organism affects the substance
bio: the amount of substance at sites of biological effect at various times after application or exposure

pharmacokinetics determine bioavailability (how does the substance get it in, where does it go, how does it change, how long does it stay, where does it exit

Question 9

how does adme underlie bioavailability (use weed as an example)

Answer 9

bioavailability describes the rate and extent to which a substance is absorbed by the organism and becomes available at the site of action. pharmacodynamics related to concentration at soa.

weed: look at the route of administration. if you inhale, it goes to the brain. if you eat an edible, it goes through the gut, gets metabolized, and distributed to the brain with lower concentration. so the time for THC to get to the site of action (brain) will be different

Question 10

why is blood / urine used as an acceptable proxy

Answer 10

it is usually difficult to measure concentration at the soa so blood/urine are acceptable.

esp for blood, we know it has access to the site of action

Question 11

what is pharmacodynamics are the four factors that it includes

Answer 11

define: how the substance affects the organisms
factors: determined by bioavailability, mechanism of action, site of action, dose-response relationships

Question 12

what is general pharmacodynamics

Answer 12

common processes in most responses

Question 13

what is specialized pharmacodynamics

Answer 13

specialized to a group

Question 14

define mec, mtc, auc

Answer 14

mec: minimum effective concentration
mtc: minimum toxic concentration
auc: area under the curve

Question 15

define cmax on a pharmacodynamics curve

Answer 15

cmax is the highest concentration -> it is measure of efficacy and toxicity

Question 16

define the duration of action on a pharmacodynamics curve

Answer 16

from onset time to when the curve goes under the mec.

Question 17

what is the goal of therapeutics with reference to the pharmacodynamic curve

Answer 17

give treatments that stay within the therapeutic range. you want it so that by the time its falling, the new dose will be contributing to make sure you do not stop feeling the effects + also do not go above the toxic effects

Question 18

explain how blood pressure is regulated by calcium blockers.

Answer 18

normally, calcium rushes in, intracellular signalling, muscle tightening, drives blood pressure up. with the calcium blocker, it will bind to and block the channel -> muscles will not tighten

Question 19

what are the 3 steps of dose response and how does variability affect tolerance?

Answer 19

dose -> pk/pd -> response(s)

variability and modifying factors in these three steps are the reason why we are not all tolerant or sensitive in the same way to kinetics

Question 20

what are the 4 parts to pharmacokinetics and 3 parts to pharmacodynamics

Answer 20

kin: absorption, distribution, biotransformation (metabolism), excretion
dyn: receptor binding, signal transduction, physiological effect

Question 21

what is the difference between toxic research and pharma research

Answer 21

toxic uses model systems, pharma uses clinical systems

Question 22

what is important about the way concentration is handled in toxicology

Answer 22

toxicology references toxins. so in terms of concentrations, there is a different starting point and end goal compared to pharmacology.

toxicology starts with an exposure assessment and ends with mitigating the risk

Question 23

describe the 6 steps going from exposure to disease

Answer 23

exposure -> internal guess -> biologically effective dose -> early biological effects -> altered structure/function -> disease

Question 24

what are four properties of an organism that are essential for life

Answer 24

1. cytoplasm
2. nucleoid
3. cytoplasmic membrane
4. ribosomes

Question 25

what are four properties of organisms that have evolved to help us navigate the environment

Answer 25

1. capsule 2. cell wall 3. pilli 4. flagella

Question 26

explain the hierarchy from cells to tissues to organs to systems

Answer 26

cells organized into tissues. tissues perform special tasks and group together to form organs. several related organs work together to form a system

Question 27

how does the human anatomy factor the workings of a drug

Answer 27

there are differences in ph, gene expression, barriers that substances need to pass through. each one must be manufactured to get to the proper soa

Question 28

what are 2 things that happens in organismal fluids

Answer 28

reactions and metabolism

Question 29

what makes water essential to life on hearth

Answer 29

helps things move, we can also manipulate water with osmotic pressures and changes in environmental conditions

Question 30

explain the three parts of extracellular fluid

Answer 30

interstitial fluid: flows around the outside of cells, permitting exchange of materials. surrounds cells, facilitates exchange between inside and outside plasma: is the fluid within the bloodstream, in blood vessels and cells lymph: is interstitial fluid collected and transported by the lymph system; emptied back into blood

Question 31

explain what intracellular fluid is, where does it come from, and how does it help cells hold their shape

Answer 31

fluid found inside cells, medium in which all cell reactions take place, its pressure helps the cells to hold their shape → impacts on health, is drawn from the extracellular fluid

Question 32

explain the components of blood and where it travels

Answer 32

components: water, red & white blood cells, nutrients, platelets, proteins, xenobiotics, etc. travels within arteries, veins, capillaries, heart chambers

Question 33

what is lymph

Answer 33

interstitial fluid collected, transported, then emptied into the blood → anything in the extracellular fluid that cant get into the cells, gets back into blood and recirculated to either get eliminated or into organs that allow for the passage

Question 34

give an example of a compartmentalized fluid and secretion

Answer 34

compartmentalized fluid -> amniotic fluid secretion -> bile/saliva/urine

Question 35

what percentage of the body is intracellular fluid and extracellular fluid

Answer 35

2/3 in human is intra . 1/3 in human is extra

Question 36

if a substance gets into body, depending on __________, it will be __________ different ways

Answer 36

1. how it gets in 2. distributed in

Question 37

what is the significance of different ph levels in the body

Answer 37

ph in body is well stabilized, but not so true for stomach and urine → difference in phs in compartments → important for proteins being in different conformations, important for CHARGE

Question 38

what are 4 different types of defense mechanisms

Answer 38

Physical, chemical, enzymatic, immunological

Question 39

give an example of each type of defense mechanism

Answer 39

- physical like biological - chemical like antioxidants - enzymatic like changing structures so its more likely to leave body or less active - immunological like virus bacterial infections anyway responses that allow us to protect ourselves

Question 40

delete

Answer 40

?

Question 40

what 4 health factors make organisms less able to defend themselves

Answer 40

- Stress - Aging - Organ function - Disease / degeneration

Question 41

what 6 physiochemical factors influence the absorption of a substance

Answer 41

- state (gas, liquid, solid) - size / shape / MW → going to affect how it goes through membranes and proteins - lipophilicity / hydrophobicity - ionization state / pKa → charged or uncharged - binding and charge distribution → what types of atoms and their properties - specific structural motifs → lipids vs proteins vs dna and rna all have shared motifs

Question 42

what 2 matrix properties affect the absorption of a substance

Answer 42

- source - eating coffee vs eating the coffee bean → bean has fiber and antioxidants → so whats coming in with the substance is different - formulation - like picking a drug for your headache → changed how the drug is being delivered to your stomach - rapid relief is dissociating and absorbing quickly - some thing else might be releasing it slowly over time

Question 43

what is a cell membrane

Answer 43

cell membrane = semipermeable lipid, numerous aqueous channels, specialized carrier molecules.

Question 44

what is the difference between diffusion, active transport, and endocytosis/exocytosis/pinocytosis

Answer 44

diffusion = Passive (simple) or facilitated. passive nothing no energy, facilitated means theres a transporter. active transport = need energy, moving against concentration gradient → only to do it to pump desired things and undesired things out → evolved. drug wil only go in if the body thinks its something thats been in before, it mimics substances that usually go in Endocytosis, exocytosis, and pinocytosis = all require energy and form of active transport

Question 45

what is simple diffusion driven by

Answer 45

Driven by concentration gradient across a membrane separating two compartments passive = no energy input no saturation limit no protein carrier

Question 46

Most drugs and toxins enter organisms by ________

Answer 46

passive diffusion

Question 47

how do lipid soluble substances move across biological membranes

Answer 47

Lipid soluble substances move easily across most biological membranes – ‘dissolve’ in lipid components

Question 48

how do water soluble substances cross cell membranes

Answer 48

Water soluble substances can cross cell membranes through aqueous channels or pores – size dependent

Question 49

which diffuse more readily, non-ionized or ionized substances

Answer 49

Non-ionized substances diffuse more readily across membranes than ionized substances

Question 50

define hydrophobicity and lipophilicity

Answer 50

Hydrophilicity* = represents the affinity of a molecule or moiety for an aqueous environment. Lipophilicity = represents the affinity of a molecule or a moiety for a lipophilic environment.

Question 51

how is lipophilicity measured? what is a partition co-efficient and how does it work

Answer 51

Lipophilicity is commonly measured by its distribution behaviour in a biphasic system partition coefficient in 1-octanol/water = water in octanol, put substance into it and shake it and measure how much of it on each side. strongly lipophilic will all be in the oil

Question 52

what is the equation for the partition coefficient

Answer 52

concentration dissolved in partition solvent/concentration dissolved in water

Question 53

what do weak acids and weak bases have the capacity to become

Answer 53

weak acid and weak bases have capacity to become charged based on environment, live in equilibrium in charge and uncharged protonated and deprotonated form following henderson

Question 54

what does the ratio of ionized to unionized forms of drugs depend on

Answer 54

compound‘s acid dissociation constant and pH of the environment

Question 55

explain the dissociation equation for HA

Answer 55

- Acidic chemicals (HA) dissociate to release H+ and a charged anion (A-): - HA ↔ H+ + A- - protonated acid is uncharged - when its dissociated then its negatively charged - HA gets through membranes than A-

Question 56

explain the base dissociation equation

Answer 56

Basic chemicals (BH+) also dissociate to release H+ but and uncharged base (since protonated form is usually charged) BH+  ↔ B + H+ with a base its the opposite bc when its protonated then its charged

Question 57

what happens when pKa = pH

Answer 57

when pKa = pH: [A-] = [HA] and [BH+] = [B]

Question 58

what is the distribution coefficient

Answer 58

same thing as partition, except that it takes into account charge

Question 59

what direction does passive transport move molecules

Answer 59

in the directions of the electrochemical gradient

Question 60

what direction does primary action transport move molecules

Answer 60

against the direction of electrochemical gradient

Question 61

what kind of molecules work through simple diffusion and what is it driven by

Answer 61

lipophilic, small, neutral better than the opposite for passing through membrane, it is driven by concentration gradient across a membrane separating two compartments

Question 62

is energy required for simple diffusion, is there a saturation limit, is there a protein carrier

Answer 62

no to all of them

Question 63

how do most drug and toxins enter the body

Answer 63

through passive diffusion

Question 64

explain how all three substances cross membranes: lipid soluble, water soluble, non-ionized substrance

Answer 64

Lipid soluble substances move easily across most biological membranes – ‘dissolve’ in lipid components Water soluble substances can cross cell membranes through aqueous channels or pores – size dependent Non-ionized substances diffuse more readily across membranes than *ionized* substances

Question 65

what is lipophilicity measured by and what is the partition co-efficient made of

Answer 65

lipophilicity is commonly measured by its distribution behaviour in a biphasic system part co: 1-octanol/water

Question 66

what molecule define lipophilicity and what molecule casues toxicity

Answer 66

lip: CH2 tox: O2

Question 67

what happens are you increase the hydrocarbon chain in terms of lipophilicity and crossing membrane

Answer 67

as you increase hydrocarbon chain, and lipophilicity, gets through membranes more effectively, and less concentration needed of substance

Question 68

increasing lipophilicity = increasing ___________

Answer 68

toxicity

Question 69

what 2 things determine if a molecule is neutral or in its ionized state

Answer 69

depending of the pka and the ph of the fluid will determine if its neutral or if its in its ionized state

Question 70

what happens when an acids pH is below pKa and what happens when an acids pH is above pKa

Answer 70

pH < pKa = protonated = membrane soluble pH > pKa = charged form = not membrane soluble

Question 71

what happens when a base pH is below pKa and what happens when a base pH is above pKa

Answer 71

pH < pKa = deprotonated = not membrane soluble pH > pKa = protonated = membrane soluble

Question 72

what is strychnine, and also explain the example of it being injected into rats

Answer 72

strychnine = weak base, neurotoxin, antagonist of glycine and acetylcholine receptors, affecting motor nerves in the spinal cord rats: they manipulated the pH of the stomach (usually it is at pH 2, they made it more basic). the more basic they made the rat, the faster it died after being injected with the strychnine. this is because at more basic pH, the interval to death becomes quicker since the strychnine was in its charged form. when the rat was more acidic, the base was mostly undissociated, and protonated, letting the rat survive.

Question 73

what are three key points of a simple diffusion channel and explain each one

Answer 73

1. passive = no energy input, it follows the concentration gradient as long as the pores are open 2. selective = regulated, only allows specific molecules 3. non-saturable = can be regulated (increasing concentration of one way) or inhibited by a blockade (all will be let through the pores, there will just be a transit time)

Question 74

describe the structure of the facilitated diffusion channel (outside of protein, pore)

Answer 74

outside of protein = lots of lipophilic amino acids pore = certain diameter + shape which is determined by the 3d structure of it and the amino acids. can be selective in terms of size and charge

Question 75

describe the features of the facilitated diffusion – carrier mediated

Answer 75

- carrier proteins/transporters require energy but across a concentration gradient - channel never changes structure, but there is a lock-and-key recognition that bins glucose to the lock and then there is a 3d interaction with amino acids that cause conformational changes making the top/bottom open

Question 76

describe the six factors of facilitated diffusion with carrier proteins

Answer 76

1. specialized transport = transports nutrients that the body uses 2. passive = no energy input, follows gradient 3. selective 4, 5. reversible and saturable = if you keep pumping glucose on the extracellular side, it takes time for the stuff to open and close for amino acids to cause the conformational change from open to close - also not enough transporters - so you can saturate the activity of transporters even if energy isnt involved 6. can be inhibited by blockage = competition or blockade can happen OR there can be mimic/analogues of the metabolites

Question 77

where is facilitated diffusion with protein carriers found most commonly

Answer 77

fetal tissues like glucose

Question 78

describe the seven elements of active transport

Answer 78

1. specialized transport = nutrients against the gradient 2. energy dependent = protein pump transporter 3. selective = only molecules that fit into the active site and induce conformational changes will go 4. reversible 5. saturable = only certain number can cross through, can be inhibited by competition 6. can be inhibited by "blockade" 7. xenobiotics may mimic endogenous molecules

Question 79

what do primary active transporters and secondary active transporters do

Answer 79

Primary Active Transporters generate stored energy for subsequent use (e.g. ATP hydrolysis to create gradient) Secondary Active Transporters utilize energy stored in voltage and ion gradients generated by a primary active transporter (e.g. NA+/K+-ATPase & sodium-dependent glucose transporter)

Question 80

how can xenobiotics be competitors for the endogenous transport molecule in protein carrier mediated active transport

Answer 80

1. protein carriers have to actually recognize xenobiotics = this is because they open share structural properties (size, planarity, charge distribution) and/or structural motifs with carrier’s endogenous (co-)transport molecule. 2. pumps will let things in that are evolutionary good for us and some will pump out the bad things. any xeno that looks like a glucose will be let in by a glucose transport pump

Question 81

what are the two major drug transporters

Answer 81

1. ATP-Binding Cassette transporters (ABC) super-family 2. Solute Carrier (SLC) transporters

Question 82

explain how atp bc works and give an example of it

Answer 82

- primary active transport - works against bioavailability example: P-glycoprotein “pump” , it mediates efflux of solute from the cytoplasm

Question 83

explain the details of slc transporters

Answer 83

- secondary active transport - organic anion transporting polypeptides - organic cation transporters = they mediate distribution, metabolism, and excretion of xenobiotics

Question 84

what are the three types of endocytosis

Answer 84

1. phagocytosis 2. pinocytosis = anything thats dissolved and gulped will get into cell and even pass through maybe through to other side. it is non-selective = everything dissolved will be absorbed 3. receptor-mediated endocytosis = in absorbing large fatty molecules, common way for larger xenobiotics get into blood stream. more targeted