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Foundations of Medicine > Week 4 Objectives > Flashcards

Week 4 Objectives Flashcards

1
Q

Negative Feedback process to control body temperature

A

• TOO HOT
o Blood warmer than set point
o Sweat glads activated, secrete perspiration, vaporized by body heat helping the body cool
o Also skin blood vessels dilate, capillaries become flushed with warm blood, heat radiates from skin surface
o Body temp decreases, blood temp declines, and hypothalamus heat-loss center “shuts off” (negative feedback)
• TOO COLD
o Blood cooler than set point
o Skin blood vessels constrict, blood is diverted from skin capillaries and withdrawn to deeper tissues, minimizing overall heat loss from skin surface

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2
Q

What is the equation describing the two factors that control blood flow through a vessel

A

Flow = (pressure difference)/resistance
Q=ΔP/R
Q=flow rate (volume/time)
∆P=pressure difference (mmHg)
R=resistance to flow (mmHg x time/volume)
Circulatory flow=caridac output from the heart pump (stroke volume X heart rate)
Resistance= result of frictional forces as blood passes through the consecutive segements (artery, arteriole, capillary, veins) and is called the total peripheral resistance (TPR)

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3
Q

Identify the two factors that control the mean arterial pressure and indicate what effect changes in these factors will have on mean arterial pressure.

A
  • Mean arterial pressure (MAP) = CO x TPR
  • CO= cardiac output
  • TPR= Total peripheral resistance
  • MAP (BP) IS THE CONTROLLED VARIABLE (needs to be maintained at 100 mmHG for adequate brain blood flow)
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4
Q

Identify the two factors that influence cardiac output (CO)

A
  • Heart rate

* Stroke volume

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5
Q

Describe the negative feedback role of arterial baro-receptors in the regulation of arterial pressure

A

Blood pressure drops below normal range
• Baroreceptors are inhibited
• Decreased impulses from baroreceptors activate centers
• Increase in sympathetic impulses to heart cause (increased HR, increased contractility, and increased CO)
• Vasomotor fibers stimulate vasoconstriction, increasing Resistance (R)
• Increased CO and Increased Vasorestiction restore BP

Blood pressure above normal range
• Barorecptors are stimulated
• Decreased sympathetic impulses to heart cause decreased HR, decreased contractility and decreased CO
• BP returns to normal

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6
Q

Identify the primary homeostatic roles of the cardiovascular system.

A

• To provide mass transit system to move materials around the body and an exchanges surface for the movement of materials into and out of the vascular space

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7
Q

Mechanistic Vs. Teleologic

A

Mechanistic- how events happen, cause and effect

Teleologic- why events happen- explain purpose

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8
Q

Divisions of Nervous System

A

oCentral- Brain and Spinal Cord- responsible for integrating, processing, and coordinating sensory data and motor commands
oPeripheral- everything else outside CNS
• Sensory Division (afferent)- Brings information to the CNS from receptors in peripheral tissues and organs
• Motor Division (efferent)- carries motor commands from the CNS to peripheral tissues and systems
-Somatic- motor neurons mediate voluntary movement
-Autonomic- nervous system mediated involuntary movement
o Parasympathetic- rest and digest (anabolic)
o Sympathetic- fight or flight (catabolic)

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9
Q

Identify 3 benefits of personalized medicine

A

o Safer drugs (reduction of side effects)
• Warfarin example
o Increased drug effectiveness (able to use less)
o Alternative drugs for “standard treatments”
o Dosages based on an individuals genetics
• Individuals who metabolize a drug too quickly to benefit from any effect

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10
Q

Describe genetic tests that may be used for detecting genetic varients (SNPs)

A
  • Deep sequencing (rapidly increasing)- know every piece of DNA or RNA
  • Exon Trapping
  • Direct sequencing (most common)
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11
Q

Describe general role of cytochrome p450 gene family

A

o Cytochrome p-450 enzymes: contribute to the metabolism of approx.. half of all medications (ex. Codeine, acetaminophen, cyclosporine A, erythromycin)

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12
Q

Summary of 2D6/3A4

A

o More 2D6 than 3A4 = can convert codeine into morphine
o More 3A4 than 2D6 = cannot convert codeine (makes norcodeine)
o Grapefruit Juice= reduces 3A4
o Quinidine= reduced 2D6

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13
Q

What do 3A4 and 2D6 do?

A

o 3A4 is an essential enzyme (need at least one functional copy)- converts “codeine” to “norcodeine” which cannot be used by the body
o 2D6- one enzyme that is required for the metabolism of codeine to morphine

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14
Q

Describe 3 different metabolizers and the significance of pain management with difference of 2D6

A

o Poor metabolizer- genetic predisposition or polymorphism that blocks the metabolism of certain drugs, may over does on less because it can not be metabolized
o Extensive metabolizers- allows them to effectively metabolize codeine to morphine
o Ultrarapid Metabolizers- metabolizes too quickly to be able to effectively benefit from the medication (codeine-derivative medications provide no pain relief)

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15
Q

When is genetic test needed prior to administering cancer therapy?

A

o to give targeted therapies must know if mutation (biomarkers) exists
o Not naturally SNPs
o Very expensive therapies

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16
Q

Define receptor and it’s funcitons

A

macromolecule within or expressed on the surface of a cell
Functions-
Recognition of drug/ ligand (infers selectivity)
Signal Transduction- recognition of the drug needs to be communicated to the cell

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17
Q

What are the four major mechanisms of receptor-mediated signal transduction?

A
  1. G-protein coupled receptor
  2. Ligand gated Ion Channels
  3. Receptors as enzymes
  4. Receptors regulating nuclear transcription
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18
Q

What are some major attributes of drug receptor-mediated processes?

A
  • highly compartmentalized
  • self- limiting
  • organized into opposing systems
  • provide opportunities fro signal amplification
  • operate through small number of 2nd messenger systems
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19
Q

What are the two underlying assumptions of the drug occupancy theory?

A
  • effect of the drug is proportional to receptor occupancy

- interactions are monovalent (one receptor binds one ligand)

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20
Q

Distinguish the differences in drugs that are full agonists, partial agonists, and antagonists

A

Full agonist- maximal response, has full efficacy (alpha=1)
Partial Agonist- produces less than maximal response but has partial efficacy ( 1>alpha>0)
Antagonist- has affinity for receptor that inhibits action of agonist, has no efficacy (alpha=0)

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21
Q
  1. Define and distinguish the terms affinity, efficacy, EC50, and potency as they pertain to drugs
A

• EC50- Half maximal effect, what concentration of drug can we elicit half of our total effect
• Affinity- ability to form complex with its receptor (1/KD)
o The greater affinity the lower the drug concentration required to produce an effect
o Basis of receptor classification
• Efficacy/Intrinsic Activity- capacity to produce response
• Potency- relative position of dose-response curve
o It is a ratio, a COMPARISON to some standard (takes less of drug to get same effect as other drug = more potent) → doesn’t have to do with SIZE of response
o Not the amplitude of response

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22
Q
  1. Distinguish between competitive, noncompetitive, and physiological mechanisms of drug antagonism
A

• Competitive Antagonist-
o Reversible
o Dose response shifts to right
o Apparent affinity of agonist is reduced
o Slope does not change
o Maximal response can still be produced
• Non competitive-
o Irreversible
o Maximal response reduced
o Apparent affinity changes very little, if at all
o Apparent number of receptors decreased.. for the near time, they are “gone”
• Physiological mechanisms of drug antagonism (looking at systems)- involves interactions among regulatory pathways mediated by different receptors

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23
Q

Inverse agonism

A

creates a reverse or lesser affect of the receptor

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24
Q

Generally describe the two-state theory of drug-receptor interactions

A
  • Receptors can exists in multiple forms (active/ inactive) both in equilibrium
  • Level of active receptor is proportional to basal effect
  • If add agonist, agonist stabilizes receptor into active form
  • Inverse Agonist
  • Antagonist- not shifting equilibrium
  • Partial Agonist- weak affinity for active form of receptor
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25
Q

What is quantal log dose-response curves? What can it show you?

A

• All or nothing responses
• ED50- median effective dose (dose producing effect 50% of populationo CAN see median effective does
o CANNOT determine KD or maximal efficacy

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26
Q

What is therapeutic index?

A

Measure of relative safety

Ratio of LD50 to ED50 (how much it takes to kill half/ how much it takes to work on half)

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27
Q

Respiratory System

A

Distribution of Oxygen to tissues
Transport of CO2 from tissues
Regulated by pH receptros/ [CO2]

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28
Q

Urinary System

A

Regulation of blood palsma composition- pH, electrolytes, water, osmolarity
Osmoreceptors in hypothalamus to see how concentrated blood is, ADH, more water reabsorb

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29
Q

GI System

A

digest, absorb, excretion, secretion-enzymes fluid, motility

Regulated by parasympathetic (acetylcholine) long reflexes coming from CNS AND short reflexes in gut

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30
Q

Reproductive System

A

propagate species
produce gametes
support development of fetus and infant (lactation), hormone production
Hormonally controlled by hypothalamus

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31
Q

Major mechanisms for transport of drugs across membranes

A 
passive diffusion
filtration
endocytosis
facilitated diffusion
active transport
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32
Q

Passive Diffusion

A 
does not require energy input
energy provided by gradient
goes both ways until equilbrium
DOES NOT SATURATE (reach max flux)
Not inhibited by structurally similar compounds, every compound behave independtly
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33
Q

Bulk flow transportation methods

A

Filtration and Endocytosis

34
Q

Facilitated Diffusion

A

movement down electrochemical gradient, facilitated by a protein?

35
Q

Active transport

A

movement AGAINST gradient
requires energy
Primary (ATP hydrolysis)
Secondary (coupled to another compounds gradient)

36
Q

ATP- Binding Cassette (ABC) super family

A

primary active transport
moves substance out of cells or into organelles
(many cancer cells have over expression of MDR1 and it makes them resistant to chemotherapy
*selective and inhibited by closely related compounds** can account for drug toxicities, drug drug interactions, and inherited susceptibilities

37
Q

Solute Carriers (SLC) Superfamily

A

secondary active transport mechanism, and facilitated diffusion?
Move substances into or out of cells
Drugs interfere with ability to re-uptake, prolongs neurotransmitter in enviornment (serotonin)
*selective and inhibited by closely related compounds ** can account for drug toxicities, drug drug interactions, and inherited susceptibilities

38
Q

o Use Fick’s law to identify factors that control drug transport across a membrane by passive diffusion

A

Flux= DAK/∆X (Cout-Cin)
Concentration gradient (Cout –C in)
Diffusion constant (inversely proportional to size)- D
Membrane: water partition coefficient (measure of relative lipid solubility) –K
Membrane surface area – A
Membrane thickness- delta X
Permeability constant- P = DAK/∆X (vol/time)

39
Q

o Describe the effect of pH on diffusion of weak acids and bases across biological membranes and explain how this leads to the phenomena of ion trapping

A

The pH affects the Henderson hasselbach equation
pH-pKa=log (nonprotinated/protinated)
Will determine how many protonated vs. non protonated atoms there are, and only non-ionic can transfer across the membrane
**Weak bases will get trapped in relatively acidic environments
**Weak acids will get trapped in relatively basic environments

40
Q

o Compare and contrast the two major carrier-mediated drug transport mechanisms and describe their potential importance in clinical practice

A

o Facilitated Diffusion does not require energy
o Active Transport does require energy
o Both are selective, and inhibited by similar chemicals (drug-drug interactions)
o Both can saturate at high substrate concentrations

41
Q

o Define the term bioavailability as it relates to absorption of orally administered drugs

A

o The fraction (f: from 0 to 1) of the administered dose that enters the general circulation
o IM > SC > Oral
o IV= bioavailability at 100% (f=1)

42
Q

What are the major factors that affect the internal distribution of a drug?

A
  • Relative tissue perfusion rate (higher rates in kidney, lung, liver, and brain)
  • Plasma protein binding (bound drugs do no cross membranes, albumin may bind weak acids)
  • Partitioning between plasma and tissue (pH and ion trapping, tissue protein binding, solubility)
  • Specialized barriers (blood brain barrier, placental)
43
Q

Define VD

A

volume in which a drug APPERARs to be distributed at equilibrium
VD= (total concentration of drug in body/ total concentration measured in reference compartment “plasma”)

44
Q

Drug redistribution

A

2 phases
1st- distributes to tissues with high perfusion rates
2nd- removal from sites of high perfusion rates then redistributes to tissues with low perfusion rates
*If the site of action for the drug was in a highly perfused organ, removal of the drug via redistribution will result in termination of drug action

45
Q

Define renal clearance

A

(Clr) the volume of plasma (L) that is cleared of drug the kidney per house

46
Q

What is GFR? How can you relate this to Clr to determine what is happening to the drug?

A

GFR- glomerular filtration rate, is measure of the volume of fluid filtered through the kidney per unit time
Clr= GFR then freely fitlered
Clr < GFR then filtered but the reabsorbed
Clr > GFR then filtered and secreted (adding extra compound to once being filtered)

47
Q

Describe the major phases of drug biotransformation

A 
o	Phase 1 Reactions- 
•	Add or expose functional groups
•	Oxidation most common reaction
•	CYP system (P450)
•	Metabolize approx 75% of known drugs
•	Metabolites may cause function or alter activity of CYP
•	Localized to smooth ER
•	Metabolites generally more polar
•	Metabolites may be active or inactive
o	Phase 2 Reactions-
•	Conjugation with charged species
•	Glucuronidation most common reaction
•	Acetylation, sulfate conjugation, methylation, glutathione conjugation
•	Metabolites generally more polar
•	Inactivation usually results
•	Addition of large anionic groups to detoxify reactive electrophiles
48
Q

List the major organs of drug biotransformation

A 
LIVER! main
GI tract
kidney
lungs
skin
plasma
49
Q

What are the two major functions of the pentose phosphate pathway?

A

Generation of NADPH

Generation of 5 carbon sugars

50
Q

What are the two phases of pentose phosphate pathway?

A

i. The oxidative phase
1. Coverts glucose 6-phosphate to ribulose 5-phosphate
2. Generates NADPH + H+ (and CO2)
3. Reactions are NOT reversible
ii. The regenerative phase
1. Converts ribulose 5-phophate to the glycolysis intermediates (fructose 6-phosphate and glyceraldehyde 3-phosphate)
2. Glycolysis intermediates can be used to generate five carbon sugars for nucleotide synthesis
3. Reactions ARE reversible

51
Q

Why are the products of the pentose phosphate pathway important?

A

Ribulose 5-phosphate: nucleotide synthesis

NADH- maintains glutathion in a reduced state so that it can remove hydrogen peroxide from the cell

52
Q

Fructose metabolism

A

Fructose (fructokinase)
fructose 1-phosphate (aldolase B)
dihydroxyacetone phosphate & gyceraldehyde 3-phosphate

-both can get converted into glyceraldehyde 3-phosphate can enter glycolysis or gluconeogenesis/glycogenogenesis

53
Q

Essential Fructosuria

A

o Benign
o Autosomal recessive
o Fructose in urine
o Fructokinase is deficient- no hepatic conversion, hexokinase picks up the slack or excess can be excreted in urine

54
Q

Hereditary fructose intolerance

A

o Aldolase B deficiency (hepatic)
o Fructose 1-phosphate has NO METABOLIC FATE
o Traps cellular phosphate on fructose (phosphate flux is critical)
• Halts ATP synthesis → no phosphate available for glycolysis
• Hypoglycemia → no gluconeogenesis
• Lactic Acidosis → maybe, glycolysis ramped up in response but also requires ATP
o Asymptomatic until fructose is ingested
o If untreated
• Recurrent hypoglycemic episodes associated with consuming fructose
• Failure to thrive
• Hepatic failure

55
Q

Galactose 1-phosphate uridyl transferse deficiency

A

o Classical galactosemia
o Can’t convert galactose 1-phosphate to UDP-galactose & glucose 1-phosphate
o Autosomal recessive, very serious
o Causes jaundice, hepatomegaly, hypoglycemia, lethargy, FTT
o Treatment- eliminate ALL galactose from diet

56
Q

Galactokinase deficiency

A

o Galactose accumulates → converted to galactitol through polyol pathway → cataracts
o Treatment → eliminate galactose

57
Q

Uridine diphosphate galactose 4-epimirase deficiency

A

o Benign form- only affect leukocytes and erythrocytes
o Serious- all tissues, similar to transferase deficiency
o Can’t convert UDP-galactose to UDP- glucose
o Treatment → restricted galactose in diet (still need some because need UDP-galactose)

58
Q

Glucose 6-phosphate dehydrogenase deficinecy

A

o Hemolytic anemia due to oxidative stress
o 1st enzyme in pentosephosphate pathway → inhibits all other reactions
o Don’t have enough NADPH, not getting enough glutathione in reduced form, can’t handle oxidative stress
o Oxidative stress causes increased ROS and hydroxyl radical causes damaged to DNA, cell membrane, ect → results in hemolysis
o Clinically hidden until oxidative stress then hemolytic anemia
o X-linked recessive trait, deficiency causes slower rate of enzyme (enough to make nucleotide, but not antioxidant capacity)
• Sulfa drugs (for UTIs)

59
Q

Differentiate between pharmacodynamics and pharmacokinetics

A

Pharmacodynamincs- effect of drug on body

Pharmacokinetics- effect of body on drug

60
Q

VKORC1

A

PharmDynamic
Enzyme that reduces Vitamin K to combine with inactive clotting factors. Warfarin inhibits this enzyme. Mutation in this produces less enzyme that warfarin acts on. Warfarin is MORE effective, administer LESS

61
Q

CYP2C9

A

PharmKinetic
Cytochrome p450 that metabolizes warfarin. Mutation raises Km, slows down metabolism of warfarin. Warfarin stays in system longer. MORE effective, administer LESS

62
Q

Effect of green leafy veggies on warfarin

A

PharmDynamic
increases reduced vitamin K, able to produce more active clotting factors. Makes warfarin LESS effective, administer MORE

63
Q

Antacids effect on warfarin

A

PharmKinetic

Changed pH, decreased uptake of warfarin. Make warfarin LESS effective, administer MORE

64
Q

Glipizide effect on warfarin

A

PharmKinetic
competes for plasma binding protien –> less warfarin bound, more free, more effective, administer LESS drug
Also competes for oxidation, makes warfarin metabolized slower, more in system. more effective, administer LESS drug

65
Q

Cidmetide effect on warfarin

A

PharmKinetic

cyp2CP inhibitor, decreases metabolism, more effective, administer LESS

66
Q

Rifampin

A

PharmKinetic

induces cyp2CP, increases metabolism of warfarin, less effective, administer MORE

67
Q

How do you determine VD?

A

Vd= total drug/ [of drug in plasma]

68
Q

What is the elimination constant and how can you find it?

A 
Ke= constant fraction of drug eliminated per unit of time- (slope of elimination curve).
Ke= (Cl/Vd)
69
Q

What is drug clearance?

A

Cl= rate of elimination/ [drug in plasma]

*whole body clearance not just renal clearance**

70
Q

What can you determine from an elimination curve?

A

Ke, half life, and Cl

71
Q

Ke = ?

A

Ke= Cl/Vd

72
Q

How do you determine half life?

A

-slope of elimination curve
t(1/2)= 0.693 (Vd/Cl)
t(1/2)= 0.693/Ke

73
Q

What is Css? how do you find it?

A

Css -> therapeutic amount, a steady state of that concentration in plasma
Css= (drug input)/ Cl

74
Q

What is a maintenance Dose?

A

Oral dose that will produce the desired therapeutic level = amount that needs to be administered at plateau to replace drug lost during previous dosing interval
= dosing rate that achieves desired level of effect (Kin) x dosing interval (hr)/ f (bioavailibility)

75
Q

Loading Dose

A

=(Css x Vd)/ f

is a single dose which administer at the outset, will produce the desired steady-state plasma concentration

76
Q

Glucose glucose 6-phosphate

A

Glucokinase (glycolysis): glucose to glucose 6- phosphate

Glucose 6-phosphatase (gluconeogenisis): glucose 6-phosphate to glucose

Higher Km for glucokinase then hexokinase (in cells) so kinetcally directed outside of liver (can’t get made and broken down in liver)

77
Q

Fructose 6-phosphate Fructose 1,6- bisphosphate

A

PFK-1 (Glycolysis): fructose 6-phosphate to fructose 1,6- bisphosphate

Fructose 1,6- bisphosphatase (gluconeogenisis): fructose 6-phosphate to fructose 1,6-bisphosphate

Fructose 2,6-bisphosphatase and AMP- activates PFK-1, inhibits F1,6BP

78
Q

Phosphoenolpyruvate pyruvate

A

Pyruvate Kinase (glycolysis): PPE to Pyruvate

PEP-CK (gluconeogenisis): OAA to PEE

PKA- inhibits PK, acetyl CoA inhibits pyruvate dehydrogenase which diverts pyruvate to OAA and then to PEE to start gluconeogenisis

79
Q

Glucose 6- phosphatase deficiency (GSD 1)

A 
Glycogen storage disease
fasting hypoglycemia
lactic acidosis
enlarged liver
** needs to remove phosphate to get it out of liver and into periperal tissues (same as glycogen)
80
Q

Fructose 1,6 bisphosphate deficiency

A

rare autosomal recessive disorder
Episodic hypoglycemia
Can still use glycogen, but can’t do gluconeogenisis.

81
Q

What are the major sources of carbon for gluconeogenisis?

A

Lactate
Glycerol
Amino Acid

Foundations of Medicine (19 decks)

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