Week 4 - Pharmacokinetics Flashcards
Fatal Medication Errors (FME)
- 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)
Pharmacokinetics
Concentration in plasma is always changing
It is dynamic, response is always going up and down on dose-response cuve around the efficacy point
Concentration of Free Drug
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…
What are the major mechanims of drug transport?
- Passive Diffusion
- Filtration
- Endocytosis
- Facilitated Diffusion
- Active Transport
Passive Diffuesion
- 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…
Passive Diffusion main points..
- 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
Rate of Passive Diffusion
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
Effect of Ionization on passive diffusion
- 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
How do we manage ionization effects?
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..
Ion Trapping
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
Diphenhydramine is a weak base…
- 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.
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
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)
Bulk Flow Mechanisms
- 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
Carrier mediated mechanism
Facilitated Diffusion
Facilitated Diffusion
- Movement down electrochemical gradient
- Selective & inhibited by similar chemicals
- Saturate at high substrate concentrations
Carrier Medicated Mechanisms
Active Transport
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)
Carrier Mediated Mechanisms
ATP binding cassette (ABC) Super family
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..
Carrier Mediated Mechanism
Solute Carrier (SLC) superfamily
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))
Carrier Mediated Mechanisms
Both ABC and SLC are very important
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
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
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
Absorption of Drugs
- 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
Oral route of drugs
Advantages and Disadvantages
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
Bioavailability of Oral drug dosing
What is it and how to measure it
- 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 curveArea under curve/ area under curve
What is Lipinski’s Rule of 5
(oral drug dosing)
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.
SL (dosing)
Rectal
IV
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)
Distribution of drugs in body
Determinants include
- realative tissue perfusion rates
- Plasma protein binding
- Partitioning between plasma and tissues
Perfusion Rate
Where are there high, intermediate, and low rates in body?
- 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
Plasma Protein Binding
- 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)
Tissue; Plasma Partitioning
- 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)
D in ADME
Specialized barriers to Distribution
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
How to find the Apparent Volume of Distribution (Vd)
What is it?
This is a VERY important concept
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
Vd - a Critical Concept
What does it represent?
- 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. **
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: 50 mg / 1 mg/L = 50 L
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)?
- 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*
What are things that increase of decrease Vd?
- 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
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
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
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
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.
Termination of Drug Action
- Storage (redistribution)
- Excretion (as unchanged ‘parent’)
- Biotransformation (aka metabolism, although the former term is more technically correct)
Redistribution - What are the 2 phases?
- 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)
Renal Excretion (of parent compound, unchanged drug)
What are the 3 steps?
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..
Rena Clearance
- 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)
Clearance of Drug from body
What are the three methods a drug can be secreted or absorbed in kidney?
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
Biliary Excretion
Resperatory Secretion
Other Excretion Sites
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
Biotransformation of drugs
- 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
What are the differences of Phase I and Phase II biotransoformations
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
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
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
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
A - flush it out
If drug is active transporter
Then C- drug drug interaction may be effected..
What are the organs of Biotransformation?
- LIVER - first pass metabolism, most important. liver has many systems for this
Other
- GI tract - epithelium
- Kidney
- Lungs
- Skin
- Plasma
Cytochrome P450 (CYP) System
Where?
Which phase of biotransoformation?
- 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
What are the different CYPs.. What are the major ones?
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..
What are the nonmicrosomal Oxidations (P450-independent)
Monoamine & Diamine Oxidases
MAO inhibitors are a majority of the anti-depressants..
HUGE drug target.
What are phase II conjugation reactions?
- Glucuronidation
- Acetylation
- Sulfate Conjugation
- Methylation
- Glutathione Conjugation
What are inhibitors of Biotransofrmaion**
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)
Stimulation of Biotransformation **
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
Other factors altering Biotransformation
- 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)
Fast and slow acetylators.. a Binodal distribution of a populations reaponse to a drug…
Pharmacogenomic (pharmacogenetics)
- 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
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
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
