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Flashcards in Week 4 Objectives Deck (81):

Negative Feedback process to control body temperature

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)
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o Skin blood vessels constrict, blood is diverted from skin capillaries and withdrawn to deeper tissues, minimizing overall heat loss from skin surface


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

Flow = (pressure difference)/resistance
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)


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

•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)


Identify the two factors that influence cardiac output (CO)

• Heart rate
• Stroke volume


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

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


Identify the primary homeostatic roles of the cardiovascular system.

• 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


Mechanistic Vs. Teleologic

Mechanistic- how events happen, cause and effect
Teleologic- why events happen- explain purpose


Divisions of Nervous System

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)


Identify 3 benefits of personalized medicine

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


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

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


Describe general role of cytochrome p450 gene family

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


Summary of 2D6/3A4

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


What do 3A4 and 2D6 do?

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


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

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)


When is genetic test needed prior to administering cancer therapy?

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


Define receptor and it's funcitons

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


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

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


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

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


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

-effect of the drug is proportional to receptor occupancy
-interactions are monovalent (one receptor binds one ligand)


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

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)


4. Define and distinguish the terms affinity, efficacy, EC50, and potency as they pertain to drugs

• 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


5. Distinguish between competitive, noncompetitive, and physiological mechanisms of drug antagonism

• 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


Inverse agonism

creates a reverse or lesser affect of the receptor


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

• 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


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

• 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


What is therapeutic index?

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


Respiratory System

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


Urinary System

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


GI System

digest, absorb, excretion, secretion-enzymes fluid, motility
Regulated by parasympathetic (acetylcholine) long reflexes coming from CNS AND short reflexes in gut


Reproductive System

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


Major mechanisms for transport of drugs across membranes

passive diffusion
facilitated diffusion
active transport


Passive Diffusion

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


Bulk flow transportation methods

Filtration and Endocytosis


Facilitated Diffusion

movement down electrochemical gradient, facilitated by a protein?


Active transport

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


ATP- Binding Cassette (ABC) super family

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


Solute Carriers (SLC) Superfamily

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


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

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)


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

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


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

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


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

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)


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

-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)


Define VD

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")


Drug redistribution

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


Define renal clearance

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


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

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)


Describe the major phases of drug biotransformation

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


List the major organs of drug biotransformation

LIVER! main
GI tract


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

Generation of NADPH
Generation of 5 carbon sugars


What are the two phases of pentose phosphate pathway?

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


Why are the products of the pentose phosphate pathway important?

Ribulose 5-phosphate: nucleotide synthesis
NADH- maintains glutathion in a reduced state so that it can remove hydrogen peroxide from the cell


Fructose metabolism

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


Essential Fructosuria

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


Hereditary fructose intolerance

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


Galactose 1-phosphate uridyl transferse deficiency

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


Galactokinase deficiency

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


Uridine diphosphate galactose 4-epimirase deficiency

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)


Glucose 6-phosphate dehydrogenase deficinecy

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)


Differentiate between pharmacodynamics and pharmacokinetics

Pharmacodynamincs- effect of drug on body
Pharmacokinetics- effect of body on drug



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



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


Effect of green leafy veggies on warfarin

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


Antacids effect on warfarin

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


Glipizide effect on warfarin

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


Cidmetide effect on warfarin

cyp2CP inhibitor, decreases metabolism, more effective, administer LESS



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


How do you determine VD?

Vd= total drug/ [of drug in plasma]


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

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


What is drug clearance?

Cl= rate of elimination/ [drug in plasma]
*whole body clearance not just renal clearance**


What can you determine from an elimination curve?

Ke, half life, and Cl


Ke = ?

Ke= Cl/Vd


How do you determine half life?

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


What is Css? how do you find it?

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


What is a maintenance Dose?

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)


Loading Dose

=(Css x Vd)/ f
is a single dose which administer at the outset, will produce the desired steady-state plasma concentration


Glucose glucose 6-phosphate

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)


Fructose 6-phosphate Fructose 1,6- bisphosphate

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


Phosphoenolpyruvate pyruvate

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


Glucose 6- phosphatase deficiency (GSD 1)

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)


Fructose 1,6 bisphosphate deficiency

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


What are the major sources of carbon for gluconeogenisis?

Amino Acid