Pharmacokinetics (Wolff) Flashcards
What are the four basic pharmacokinetic processes?
(Mnemonic)
ADME
A-absorption (GI and blood)
D-Distribution (Blood)
M-Metabolism (liver, kidney, action sites, other)
E-Excretion (bile and urine out of body)
What factors affect Absorption
rate of dissolution
surface area
blood flow
lipid solubility
pH partitioning
Pros and Cons of oral administration
Pros: convenient, slow uniform absorption, safe, economical
Cons: destruction by low pH, poor absorption of large and charged particles, bind with GI contents, irritate intestines
Pros and Cons of Rectal administration
Pros: limited first pass metabolism, useful if oral route precluded
Cons: irregular absorption, irritation of rectal mucosa
Pros and Cons of sublingual/buccal administration
Pros: rapid absorption, avoids first pass metabolism
Cons: only small amounts absorbed at a time
Pros and Cons of IV administration
Pros: Most direct, bypasses barriers to absorption, suitable for large volumes, easy to adjust dosage
Cons: painful, immediate adverse effects, not suitable for oily substances/suspensions
Pros and Cons of IM administration
Pros: quick and easy, possible rapid absorption, may use as depot, good for oily substances/suspensions
Cons: painful, bleeding, nerve injury
Pros and Cons of Sub.Q. administration
Pros: Quick and easy, rapid aborption, good for suspensions and pellets
Cons: painful, cannot give large amounts
Pros and cons of inhalation administration
Pros: vollatile/aerosolized, rapid absorption, selivery to lungs may minimize systemic effects
Cons: variable systemic distribution
Pros and Cons of topical administration
Pros: application to specific surface for local effect
Cons: irritation
Pros and Cons of transdermal administration
Pros: controlled permeation through skin
Cons: irritation
Three ways for drugs to cross cell membranes
- facillitated diffusion (rare)
- Active transport (p-glycoprotein, gets drugs out of cells)
- direct penetration through simple diffusion (most common)
Which will cross the cell membrane better, polar or nonpolar drugs?
Nonpolar drugs readily dissolve in nonpolar substances and easily cross the cell membrane
What is an example of a polar drug?
Quaternary ammonium compounds have fixed charges and cannot readily cross the cell membrane
When are weak acids and weak bases able to cross cell membranes ?
only when in their unionized forms
Define the following:
Ka
S
F
Amount Absorbed
Ka=rate constant for absorption
S=salt factor
F=bioavailability, AUC route used/AUCiv
Amount absorbed=SxFxDose
If F=AUCroute used/AUCiv, what is AUC?
AUC is the area under the curve
where F equals the fraction of oral dose that enters the plasma
Equation for concentration in plasma (Cp)
Equation for Volume of Distribution (Vd)
Cp=SxFxDose/Vd
Vd=amount of drug in body/plasma concentration
What factors affect drug distribution?
ability of drugs to enter cells
blood flow to tissues
ability of drugs to exit the vascular suystem
Explain the significance of protein binding of drugs
Drugs are only bioactive if they are free (a=fraction unbound)
there is a finite number of protein binding sites in teh plasma, thus new addition of drugs can displace the bound drug
this can be a concern if the drug has a small therapeutic window, example: if drug is normally 90% bound and added drug displaces it so that now 80% is bound, the (a) doubled, from 10% to 20%
The BBB is a barrier to which category of drugs?
ionized or polar drugs unless they have a transporter
What is the primary site of biotransformation (metabolism)?
the liver which may activate pro-drugs but primarily INACTIVATES drugs
this is crucial for the renal elimination of lipophilic drugs which must be made more polar so they can be trapped in the renal tubular fluid
What are the two phases of metabolism?
Phase I: oxidation, reduction, hydrolysis
Phase II: conjugation
What occurs in Phase I of metabolism?
Products are made more polar by introducing or unmasking functional groups
oxidative proceses involve enzymes from SER and cytochrome p450
What is the function of CYP inducers
increase the enzyme levels, speed up metabolism of other drugs metabolized by same enzyme, lower plasma levels below MEC
examples: phenobarbitol, carbamazepine, ethanol, cig. smoke
Whatis the function of CYP inhibitors?
Inhibit enzymes
slows the metabolism of any other drug metabolzied but the same enzyme and can lead to toxic levels
examples: erthromycin, ketconazole, metronidazole, grapefruit juice
How does grapefruit juice inhibit the cytochrome p450?
Inhibits CYP3A4 enzyme in the intestinal epithelial cells thus increasing the bioavailability of other drugs metabolized by the same enzyme
What is the purpose of Phase II in metabolism?
Conjugation occurs to make the drug more water soluble and more excreable since the molecule is highly polar via glucoronidation or sulfation
Acetylation and methylation can also occur to make drugs less water soluble and to inactivate drug
What is the difference between glucuronidation and sulfation in the Phase II reaction of metabolsim?
glucuronidation is the major route of metabolism for drugs and endogenous compounds and occurs in the ER, can be induced
Sulfation occurs in the cytoplasm
What happens with oral administered drugs that effect their bioavailbility?
They undergo first pass metabolism which can greatly decrease the bioavailability of orally administered drugs
How are drugs eliminated?
renal (major)
bile, sweat, breath and breast milk (minor)
Describe the steps in renal drug excretion
- Glomerular filtration of small drugs filter out, protein bound drugs do not filter out
- Passive tubular reabsorption occurs of lipid soluble drugs and unionized weak acids/bases
- Active tubular secretion leads to elimination of protein bound drugs when they temporarily dosplace from protein near basolateral membranes of PCT
What are some factors that modify renal drug excretion?
pH dependent ionization
competiton for active tubular transport
age-GFR decreases with increasing age
What is the excretion rate?
mass eliminated per unit time; with first order kinetics, this increases as the plasma concentration increases
What is clearance?
what is total clearance?
the plasma volume from which all of the solute is removed per unit time (flow rate)
with first order kinetics, this remains constant as plasma concentrations change
Total clearance=renal clearance+hepatic clearance+other clearance
What is the Cockcroft-Gault eGFR equation
quick estmiate of creatinine clearance (eGFR) from a serum measurement of creatinine concentration
eGFR=[(140-age)xBW(kgs)/72xScr]
if female, multiply by 0.85
Why are adverse drug reactions 7x more likely in elderly patients?
drug accumulation due to declining renal function
greater severity of illness
use of drugs with a low therapeutic index
poor pt compliance
polypharmacy
presence of multiple pathologies
inadequate supervision
What are some of the consequences of drug-drug interactions?
synergy/potentiation leading to increased therapeutic and increased adverse effects
antagonism leading to therapeutic effects decreasing and decrease in adverse effects
creates a unique drug response (may be unpredictable)
Common adverse drug effects
constipation
skin rash
diarrhea
dizziness
drowsiness
dry mouth
headache
insomnia
What are some of the various mechanisms of drug-drug interactions?
directly chemical/physical
pharmacokinetic (altered ADME, issues with p-glycoprotein like MDR1)
Pharmacodynamic interactions (same receptor, different sites)
combined toxicity
Drug allergies and hypersensitivies require what event to occur?
What are common drug allergies?
Require prior sensitization and are not dose-dependent
penicillins have the most serious reactions, other common allergies are NSAIDs and sulfonamides
What drug will cause apnea of long duration if you lack plasma esterase?
Succinylcholine
What drug will cause hereditary methemoglibinemia if you lack NADH methemoglobin reductase?
Nitrites, sulfonamides, preimaquine, etc
What drug will cause increased toxicity if you have low liver actyl transferase?
Isoniazid and others
What drug will cause drug induced anemia (favism) if you lack G6P dehydrogenase?
Primaquine and others
what drug will cause acute intermittent porphyria if you lack porphobilinogen deaminase?
barbituates, estrogens, sulfonamides, chlorquine
What is an example of food affecting drug absorption?
Ca in diet can lead to precipitation of tetracyclines in the GI tract
What is an example of food/herbs affecting drug metabolism?
grapefruit juice is a CYP inhibitor and St. John’s Wort is a CYP inducer
What is an example of food affecting drug toxicity?
tyramine in wine, cheese and sausages cannot be metabolizd in the presence of MAO inhibitors leading to hyperadrenergic crisis
What is an example of food affecting drug action?
Na in diet can impact the actions of Li in bipolar disorder
How can food interfere with timing of drug administration?
food can mitigate GI upste but interfere with absorption of drugs in stomach
What are some issues with drug-herb interactions
Don’t always know the MOA of interaction so it is difficult to predict how they will influence drug; may cause diuresis, but still unpredictable
What are some heaptotoxic drugs?
lipid-lowering drugs
antiseizures drugs
tuberculosis drugs
antiretroviral drugs
oral hypoglycemics
antifungals
immunosuppresants
acetaminphen
What drugs can cause QT prolongation?
Tergenadine with erythromycin or ketoconazole
QT prolongation can lead to Torsades and vfib
Drugs are responsible for how many major fetal structural abnormalities?
<1%
must see characteristic malformations during a specific window of vulnerability with a dose dependent response
What are some examples of drug induced carcinogenesis
hard to evaluate, can take years for cancer to crop up.
cancer chemotherapy drugs assx with greatest carcinogenic potential (Tamoxifen for breast cancer, can cause uterine cancer)
DES was used to prevent SAb in high risk women but female fetuses exposed had increased incidence of vaginal and uterine cancers
ADME in neonates and infants (increased total body water)
Absorption: increased or decreased in GI decreased from IM injection
Distribution: low albumin-high levels of free drugs, BBB not developed, so drugs can enter brain
Metabolism: decresed, so must adjust dose downward
Excretion: decreased, so must adjust dose downward for drugs
ADME for geratrics (decrease in water, decrease in lean body mass, increase in body fat)
A: no changes, tends to decrease from GI
D: influenced by body comp., albumin levels also fall
M: tends to decrease but varies
E: decreases progressively from early adulthood
ADME for children over age one
ADE: similar to adults
M: much faster than adults, peaks at age 2
What is the placebo effect?
measurable, observable, or felt improvement that is not attributable to treatment
1/3 of all pt will respond to placebo and response may exceed that of some drugs
for pain, =75% of patients will respond to placebo
Physiological changes in pregnancy that affect drug therapy
decreased bowel tone and motility increases time for drug absorption
increased hepatic metabolism
RGF doubles thus increases GFR
(does all of this balance out such that pregnant people do not need changed doses?)
What type of drugs cross the placenta?
All drugs can cross the placenta, with lipid soluble drugs cross most readily
What are adverse drug reactions during pregnancy?
teratogenesis
dependence-producing drugs
drugs that change uterine tone
How to handle breastfeeding and drug adminstration
dose immediately after breastfeeding and avoid drugs with a long halflife
What are zero order kinetics
- constant amount eliminated per unit
- the drug elimination process is saturated
- consequently, the amount of drug eliminated is independent of the drug concentration
- can be written as dCp/dt=k, where it is the rate of change in plasma concentration; k is a constant in units of amount per time
- example: ethanol-rate of metabolism is rapidly saturated so it is effectively zero
What are first order kinetics?
- constant fraction is eliminated per unit time
- drug elimination process is not saturated
- the mass of drug eliminated is directly related to the drug concentration
- can be written dCp/dt=kCp where it is the rate of change in plama concentration, k= fractional rate constant in unites of time, Cp equals the plasma concentration of the drug
- This is the more typical form of drug elimination
With first order kinetics, each half life backwards does what to the concentration?
doubles it
Know these equations
kel=Cl/Vd
Cl=kelxVd
kel=first order eliminatino rate constant
Cl=clearance
Vd=is the apparent volume of distribution
Calculating clearance
Cl=SxFxDose/t/Cp
Cl=clearance
S= salt factor
F=bioavailability
t=dosing interval in hours
Cp=plasma concentration
Capicty-Limited reactions
- display zero order kinetics initially
- displays first order kinetics as the drug concentration falls
- would be seen with most drugs at high enough concentrations
- plasma concentration vs. time has a hockey stick appearance
Capacity Limited Elimination equation
rate of elimination=Vmax x C/Km + C
Vmax=max eliminatino capacity
C=plasma concentration
Km=drug concentration at which rate of elimination is 50% of Vmax
How to calculate Cpss
Cpss=dosing rate/Cl
=SxFxD/t X 1/kelxVd
What is a loading dose?
dose needed to rapidly achieve therapeutic drug concentrations for drugs with a very long half life (digoxin)
leading dose=Cpss x Vd/(SxF)
