Week 4 - Pharmacokinetics

Question 1

Fatal Medication Errors (FME)

Answer 1

• The “July effect”; FME in teaching hospitals were shown to increase by 10% above expected levels during the month of July.1 This spike in FME has been attributed in part to the large number of doctors that start their residencies at this time.
• FME constitute a leading cause of fatal motor vehicle accidents in the U.S. (probably > motor vehicle accidents)

Question 2

Pharmacokinetics

Answer 2

Concentration in plasma is always changing

It is dynamic, response is always going up and down on dose-response cuve around the efficacy point

Question 3

Concentration of Free Drug

Answer 3

Assume that free concentration of drug in plasma equal to the concentration of drug bound to receptors. It is regulated by many things, absorption, excretion, site of action, etc…

Question 4

What are the major mechanims of drug transport?

Answer 4

• Passive Diffusion
• Filtration
• Endocytosis
• Facilitated Diffusion
• Active Transport

Question 5

Passive Diffuesion

Answer 5

• Passively move across membrane due to concentration gradient*
• Remember, at any point in time drug is going both ways across membrane, BUT the NET response is the way it is moving…
• It will eventually become equilized and move to steady state…

Question 6

Passive Diffusion main points..

Answer 6

• Does not require energy input - energy is provided by the gradient
• It does not saturate (approach some maximum rate of flux) when the chemical concentration gradient is large
• It is not inhibited by structurally similar compounds – every compound behaves independently

Question 7

Rate of Passive Diffusion

Answer 7

Respresneted by the FIck equation

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

Know what flux is proportional to and what is it iinversely proportional to (if size of membrane is doubled.. what will happen to flux)

It is directly proportional to P

Question 8

Effect of Ionization on passive diffusion

Answer 8

• Ionized compounds do not cross membranes very well (not soluable in membrane - lipds)
• Neutral compounds DO cross membrane (they are somewhat soluable)
• Acid is a proton donor
• Base is a proton Acceptor
• So many drugs are weak acids or weak bases.. if they accept or give up a proton it will effect how they cross the membrane

Ion trapping - if there is a pH gradient, compounds will be ‘trapped’ on one side of membrane or the other

Question 9

How do we manage ionization effects?

Answer 9

Use Henderson-Hasselbach equtation

So if we know the pH we can calcualte the concentrations of inoized and neutral forms of weak acids and weak bases..

Question 10

Ion Trapping

Answer 10

Concentration may differ on either side of membrane.. how does this effect weak acids adn bases..

So on right side there is a million of the protinated Base for each neutral Base.. There are 500,000 times more of drug (BH) on the right side - they are trapped

• Weak bases will tend to be trapped in realitively acidic environments
• Weak acids will tend to be trapped in realitively basic environments

Question 11

Diphenhydramine is a weak base…

Answer 11

• Approximately 70% of drugs in current use
  are weak bases
• A weak base (pKa = 8.98) due to the primary amine group, it is > 95% ionized at physiological (7.4) pH.

Question 12

The process of ion trapping provides a likely explanation for which one of the following observations? (drugs ‘trapped’ in urin as ions will be eliminated while those present in urine as the neutral form will be reabsorbed)

(sodium bicarb increases pH, ammon Cl decreases pH)

admin of sodium bicarb to increase urine pH promotes renal elim of weak base

Admin of ammonium chloride to decrease urin pH promotes renal reabsorption of weak base

admin of amm chl to dec urin e pH promoteds renal elim of weak acid

Admin o sodium bicarbo to increase urin pH promotes rena elim of weak acid

admin of sodeium bicar bo increaese urin pH promontes renal reabsor of waek acid

Answer 12

Renal elimination vs Renal absorption (in reabsorption, the neutral form will follow water back across the membrane)

A - It will be neutral so it wont be eliminated

B - Weak base will be ionized form (no absorption)

C - Weak acid wiil be neutral (absorbed)

D - YES

E - Weak acid will be ionized (eliminated)

Question 13

Bulk Flow Mechanisms

Answer 13

• Filtration - flow of fluid through a channel
• (filtration) Capillary beds have large pores (they are leaky), large particles (30,000 to 40,000 mol weights) can pass from plasma to extracellular fluid (water)
• Endocytosis - Cell wall invaginates and engulfs a volume of fluid (can be selective or non-selective)
• Opposite is exocitosis

Question 14

Carrier mediated mechanism

Facilitated Diffusion

Answer 14

Facilitated Diffusion
- Movement down electrochemical gradient

• Selective & inhibited by similar chemicals
• Saturate at high substrate concentrations

Question 15

Carrier Medicated Mechanisms

Active Transport

Answer 15

Active Transport

• Movement against electrochemical
  gradient
• Requires energy
• Primary (ATP hydrolysis) vs. secondary
  (coupled to another compound’s gradient)
• Selective & inhibited by similar chemicals**
• Saturate at high substrate concentrations**It binds a substrate, it has a binding site for a specific compound. It can bind that substrate (or similar structure, antagonist, etc)

Question 16

Carrier Mediated Mechanisms

ATP binding cassette (ABC) Super family

Answer 16

ATP-binding cassette (ABC) superfamily

• Active transporters (1° mechanism)
• Move substances out of cells or into cell organelles
• e.g., p-Glycoprotein (MDR1) (multi drug resistant protein)

p-glycoprotein is imporant… In tumor cells they over express this p-glycoprotein transporter - it actively pumps drugs out of cells..

Question 17

Carrier Mediated Mechanism

Solute Carrier (SLC) superfamily

Answer 17

Solute carrier (SLC) superfamily

• Participate in facilitated diffusion (can transport ions) and active (2º) transport
• Move substances into and out of cells
• e.g., SERT, DAT (major role in the
  nervous system, dopamine and serotonin termination (reuptake))

Question 18

Carrier Mediated Mechanisms

Both ABC and SLC are very important

Answer 18

Both (ABC and SLC)

• Pharmacologically important
• Work in concert to move compounds into and out of cells
  Work with metabolizing enzymes to facilitate drug elimination
• Targeted by specific drug therapies
  - Can account for many drug toxicities, drug-drug interactions**, and inherited susceptibilities

Question 19

What attribute of both ABC and solute carrier transporters is most likely to explain their role in many drug-drug inteactions?

Both act to transport ionized drugs across cell membranes

Both are capable of transporting compounds against their concentration gradient

Both are coded for by very large gene families

Both are selective and inhibitite by closely related compounds

Both obtain required energy from hydrolysis of ATP

Answer 19

A - True, but doesnt provide mechanism for drugdrug interactions

B - Solute carrier transporters operate through secondary mech and some through facillitated (so not accross grad)

C - No

D - YES. Idea that these are selected and inhibited by closly related compounds.. So if have two drugs with similar structures they will compete

E - Some do, but not all, SLC is facilitated

Question 20

Absorption of Drugs

Answer 20

• Most drugs are absorbed by passive diffusion
• Routes of administration
  Enteral - “via the intestines”
  Parenteral - “outside the intestines”
• Realative rate of uptake: IM >_ SC >_ Oral, takes longest for oral to be absorbed

Question 21

Oral route of drugs

Advantages and Disadvantages

Answer 21

Advantages

• Easy admin
• Cheap
• Safety
• Good pt compliance

Disadvantages

• Some drugs are destroyed in GI tract (too acidic)
• 1st pass metabolism (liver acts on oral drugs before it even hits systemic circulation)
• Variable rate - Rate of uptake is variable - GI tract is ‘on demand’ depending on when ppl eat

Question 22

Bioavailability of Oral drug dosing

What is it and how to measure it

Answer 22

• Fraction (f; from 0 to 1) of the administered dose that enters the general circulation
• Oral bioavailability (pharmacokinetic method) = AUC oral / AUC iv
  - where AUC refers to the area under the plasma concentration-time curve

            Area under curve/ area under curve

Question 23

What is Lipinski’s Rule of 5

(oral drug dosing)

Answer 23

Most drugs exhibiting good bioavailability possess the following attributes

• Not > 5 H-bond donors (O or N with 1 or more H)
• Not > 10 H-bond acceptors (total O or N)
• Molecular mass < 500
• Octanol:water partition coefficient (log basis) < 5

• Describes a relatively small, moderately lipophilic molecule**

• Influential basis for evaluating potential drug candidates

If a drug violates Lipinski’s Rule of 5 it will not be produced* Drug companies want to formulate oral forms of drugs.

Question 24

SL (dosing)

Rectal

IV

Answer 24

Sub Lingual

• good becuase it often avoids 1st pass metabolism

Rectal

• often avoids 1st pass (mostly)

When something is injected IV -

• control dose perfectly, control timing perfectly, rapid form of administration, BUT once you inject it you cant take it back (if oral, there is a window of opportunity to reverse the efects.. pump it out if OD)

Question 25

Distribution of drugs in body

Answer 25

Determinants include * realative tissue perfusion rates * Plasma protein binding * Partitioning between plasma and tissues

Question 26

Perfusion Rate Where are there high, intermediate, and low rates in body?

Answer 26

* Higher Rates equals Faster Equilibrium Equilibrium is plasma concentration equlibriates with target organ/tissue... * High rates in kidney, lung, liver, brain (caviot is blood-brain barrier) * Intermediate rates in muscle * Low rates in fat and bone (so it will take a very long time for the plasma concentration of a drug to match adipose tissue concentration

Question 27

Plasma Protein Binding

Answer 27

* Bound drugs do not cross membranes\*\* * Pharmacologically inert (but may act as a “reservoir”) * Albumin (binds many weak acids) * α1-acid glycoprotein (AGP; binds many weak bases)

Question 28

Tissue; Plasma Partitioning

Answer 28

* pH and ion trapping * Tissue protein binding - some drugs have different affinities for various proteins (if drug needs to be brought around body by albumin it may fight other proteins for binding) * Lipid solubility - Lipophilic (hydrophobic) compounds, they will partition into tissues with high lipid content.. (depends on pt, muscles usually lean, liver can vary greatly)

Question 29

D in ADME Specialized barriers to Distribution

Answer 29

Blood-brain barrier * “Tight” endothelium + glial cells, endothelieal cells have a very tight junction, the water pores do not exist here like in other tissues... * May be very important clinically for conditions that involve the CNS - some drugs are tough to get in there * Does not apply to lipophilic substances - these will go right through the barrier Placental barrier * Importance often overstated * Assume that the developing fetus will see the drug you give mom

Question 30

How to find the Apparent Volume of Distribution (Vd) What is it? This is a VERY important concept

Answer 30

Volume in which the drug appears to be distributed, at equilibrium Value determined from kinetic data sets (stay tuned) \*\*So total amount of drug in body / total concentration of drug in plasma AFTER equilibrium has been established

Question 31

Vd - a Critical Concept What does it represent?

Answer 31

* VD is “apparent” and does not necessarily correspond to any “real” volume Reflects the relative affinity of drug for the whole body and plasma * Essentially represents the body as a big bag of plasma into which drugs are diluted. * **The VD is the volume of plasma that would be required to contain all of the drug in the body given the measured concentration in plasma. **

Question 32

Example of Vd.. So, imagine that you inject 50 mg of a drug which instantly distributes throughout the body resulting in a plasma concentration of 1 mg/L. Question: what is the VD?

Answer 32

Answer: 50 mg / 1 mg/L = 50 L

Question 33

How is Vd normalized for a pt population? Question: what is the normalized VD from the last example and what might this suggest about the drug under study (assume 75 kg patient)?

Answer 33

* Often normalized to b.w. (giving units of L/kg) permitting interpretations of its apparent value (e.g., comparable to plasma volume, extracellular fluid volume, total body water, etc.) So you take the Vd then divide it by the body weight to get units of mg/L.. Use original Vd but then divide by body weight. Do examples of this.. * Answer: 50 L/75 kg = 0.67 L/kg, which is approximately equal to whole-body water content\*

Question 34

What are things that increase of decrease Vd?

Answer 34

* Things that cause a drug to distribute out of plasma and into tissue increase VD while things that cause a drug to remain in plasma tend to decrease VD - Look at equation to figure above out... * Normalized values (L/kg) may vary considerably for the same drug in different individuals due to differences in relative lipid content, water content, etc., depending on the behavior of that particular drug The Vd reflects the realative affinity of the drug for certain tissues in body and the affinity for plama.. So if Vd is very LOW, the drug has a high affinity for plasma... if Vd is very HIGH it means it has a high affinity for body tissues and will not be very pressent as much in plasma

Question 35

Consider dru X that is neutral and realatively hydrophobic, Pt A is overweight and B is lean and fit. Which is true? Normalized Vd for drug X in pt A will be smaller than for B Normalized Vd for X in pt A will be larger than that for pt B Normalized Vd for drug X is unlikely to be different for Pt's A and B

Answer 35

A - Opposite **B - TRUE - lipophilic compount, will partition in adipose tissues so it will pull more drug out of plasma, raising the Vd** C - No. Fat content makes a big difference

Question 36

Consider drug X that is charged (hydrophilic) and distributes to whole body water.. Pt A is overweight, pt B is lean and fit. Which is true? Normalized Vd for drug X in pt A will be smaller than for B Normalized Vd for X in pt A will be larger than that for pt B Normalized Vd for drug X is unlikely to be different for Pt's A and B

Answer 36

**A - TRUE, the obese pt will have a lower total body water content, maybe 55-60% instead of 70-75% for a fit pt.. therefore the Vd will be slightly lower, not a profound difference** B - No C - Close, but no.

Question 37

Termination of Drug Action

Answer 37

* Storage (redistribution) * Excretion (as unchanged 'parent') * Biotransformation (aka metabolism, although the former term is more technically correct)

Question 38

Redistribution - What are the 2 phases?

Answer 38

* 1st distributes to tissues with high perfustion rates (cells that do things) * 2nd distributes to tissures with low perfusion rates (fat storage) It first goes to well perfused tissues, then over time it will redistibute to tissues with low perfusion rates and will lower the action of the drug (even though it is still in the body)

Question 39

Renal Excretion (of parent compound, unchanged drug) What are the 3 steps?

Answer 39

Regulation of Urine Composition Filtration * Drugs that are free in plasma, not bound to things like albumin they will diffuse into kidney tubule (mol weight cut off i 30-40 thousand) Reabsorption * Facilitated transport (for ionized compounds for ex) * Passive diffusion * The kidney then pulls water back out, this sets up a chemical gradient for drug to diffuese back into plasma (only works for drugs that passively diffuse) Secretion * Active transporters recognized certain substances in plasma and pump them into the concntrated urine to be excreted..

Question 40

Rena Clearance

Answer 40

* The volume of plasma being cleared by the kidney per time.. * ClR = volume of plasma (L) cleared by the kidney/hr * CU = drug concentration in urine (mg/L) * VU = urine flow rate (L/hr) * CP = drug concentration in plasma (mg/L)

Question 41

Clearance of Drug from body What are the three methods a drug can be secreted or absorbed in kidney?

Answer 41

Filtered Only * ClR = GFR = 125 ml/min (avg. adult) * creatinine, inulin * The plasma concentration of compound is equal to the urine concntration Filtered & Reabsorbed * ClR \< GFR * Many drugs * Plasma conc drug \> urine conc. * Reabsorbes substances the body doesnt want to lose.. * Also any substance that can passively difuse will be reabsorbed (conc grads) Filtered & Secreted * ClR \> GFR * p-aminohippurate (PAH) * Some are secreted and filtered so rapidly essentially all of the drug concentration is filtered out * Urine conc drug \> Plasma conc. GFR = glomular filtration rate = 125 ml/min

Question 42

Biliary Excretion Resperatory Secretion Other Excretion Sites

Answer 42

Biliary: compounds are eliminated into bile * May require metabolism * facilitated transporters to move compounds from plasma into hepatocytes and then into bile... * Facilitated (blood --\> hepatocyte) and active (hepatocyte --\> bile) transport of anions, cations, some neutral compounds * Enterohepatic circulation - Resp: * volatol anesthetics - can be blown off by lungs Other: * Sweat, tears, milk

Question 43

Biotransformation of drugs

Answer 43

* Some drugs are lipid soluble and nonpolar (drugs that are in mother will go into milk and to infant due to hight fat content) * Various enzymes transform * Metabolite generally more polar * Metabolite may be active or inactive * Biotransformation may be required to activate a drug (prodrug --\> drug can get targeted drug delivery (the biotransformation enzymes can be tissue specific - create drug at site of action OR drugs in form are not efficien - may be denatured in gut (high acidity) so they are hard to administer) Codeine --\> Morphine (and others) Prednisone --\> Prednisolone Many others

Question 44

What are the differences of Phase I and Phase II biotransoformations

Answer 44

Phase I Reactions * Add or expose a functional group (e. g., OH, NH2, SH) * Oxidation most common reaction (some reductive and hydrolytic as well) * Metabolites generally more polar * Metabolites may be active or inactive Phase II Reactions * Synthetic reactions * Glucuronidation most common reaction * Metabolites generally a lot more polar * Inactivation almost always results - it is so modified that it will not fit into any receptors anymore and is inactive in body

Question 45

Believe a drug is accumulting within an old pt to an unsafe level. Drug is eliminated in urine primarily so you measure creatinin clearance. it is 100 ml/min. What do you do? presceribe diuretic and advise pt to drink water admin sodium bicarb to make urine more basic collect more info regarding other drugs that this pt is taking consult appropriate sources to determine the mchanism by which drug is eliminated at the kidney

Answer 45

A - Drinkin water is always a good thing, prolly not a good idea to prescribe diuretic though, a diuretic might increase filtration rate but it would just dilute urine and enhance the elimination of products that would usually be rabsorbed... B - No, do not know what the drug is (ie weak base or weak acid) ion trapping.. making urine more basic trap weak acids C - Active secretion has selectivity - so could be a potential area for drug-drug interactions, so maybe, not enough info **D - We don't know enough**

Question 46

Believe a drug is accumulting within an old pt to an unsafe level. Drug is eliminated in urine primarily so you measure creatinin clearance. it is 100 ml/min (a little lower than average but typical for elderly pt). What do you do? add'l info - drug is weak base presceribe diuretic and advise pt to drink water admin sodium bicarb to make urine more basic collect more info regarding other drugs that this pt is taking consult appropriate sources to determine the mchanism by which drug is eliminated at the kidney

Answer 46

A - flush it out If drug is active transporter Then C- drug drug interaction may be effected..

Question 47

What are the organs of Biotransformation?

Answer 47

* LIVER - first pass metabolism, most important. liver has many systems for this Other * GI tract - epithelium * Kidney * Lungs * Skin * Plasma

Question 48

Cytochrome P450 (CYP) System Where? Which phase of biotransoformation?

Answer 48

* Localized to smooth endoplasmic reticulum (SER) * Responsible for Phase I metabolism of many drugs * Different CYP enzymes possess different substrate specificity * Rates differ among individuals - Concentration of CYP protein - Forms of CYP expressed

Question 49

What are the different CYPs.. What are the major ones?

Answer 49

Half of all drugs are metablized by CYP3A4 Substantial by 2D6 and 2C9 also minor CYPs like 2E1 adn 1A2 -Depends on substrate specificity for the enzymes..

Question 50

What are the nonmicrosomal Oxidations (P450-independent)

Answer 50

Question 51

Monoamine & Diamine Oxidases

Answer 51

MAO inhibitors are a majority of the anti-depressants.. HUGE drug target.

Question 52

What are phase II conjugation reactions?

Answer 52

* Glucuronidation * Acetylation * Sulfate Conjugation * Methylation * Glutathione Conjugation

Question 53

What are inhibitors of Biotransofrmaion\*\*

Answer 53

Microsomal Drug Oxidation * Selectivity involved - possible drug -drug interaction \* * Competetive inhibition * Inhibition of P450 (CYPs), cimetidine, ketoconazole, grapefruit juice Nonmicrosomal Drug Oxidation * Disulfuram - ALDH inhibition (alcoholism) * Diproniazid - monoamine oxidse (anti depressants)

Question 54

Stimulation of Biotransformation \*\*

Answer 54

Many drugs induce expression of P450 enzymes * Phenobarbital * Carcinogenic hydrocarbons * Alcohol * Rifampin Apparent drug tolerance * it takes more and more chemical to achive same pharmacologica affect * Since the enzymes are induced, the drugs will 'clear' faster and the dose will need to be increased

Question 55

Other factors altering Biotransformation

Answer 55

* Genetics * Diet (lots of things in diet are inducers and inhibitors of CYPs) * Environment * Age (kids and elderly are inhibited.. ) * Pregnancy (indction of enzymes and increased renal function)

Question 56

Fast and slow acetylators.. a Binodal distribution of a populations reaponse to a drug...

Answer 56

Question 57

Pharmacogenomic (pharmacogenetics)

Answer 57

* Study of genetic differences among individuals and how these differences give rise to differences in response to drugs * One component of an approach commonly referred to as “personalized” medicine * Tailor drug therapy to 'YOU' as an individual.. all ppl have varitations in CYPs due to SNPs

Question 58

Pt complains that prescribed medicine does not seem to be working. Circulating conc is well below desired levels (tested it in lab). Which is the explanations? Pt consumes large glass of grapefruit juice each morning Pts GFR is below normal range Pt is a smoker and works at an oil refinery Pt is taking another med which is structurally similar to the drug in question Genetic testing shows that this pt is deficient in CYP2D6

Answer 58

We are looking for something that enhances clearance of the drug.. A - This lowers CYPs (opposite) B - (this means it would decrease clearance) **C - These INDUCE CYPs - increasing clearance** D - This can only increase plasma concentration E - Dont know if this is even the enzyme, but this would only decrase clearance