Pharmacokinetics Flashcards
What is one example of where only transcellular transport is used? (no paracellular)
capillaries in the blood brain barrier
List the equation used to calculate the pH of a weak acid
pH=pKa + log (A-/HA)
List the equation for the pH of a weak base
pH=pKa + log(B/BH+)
What occurs as pH=pKa
there is an equilibrium between the ionized and unionized forms of weak acids and bases
what is the equation for the volume of distribution Vd
Vd=amount of drug/concentration,
Vd=D/Co
what is the concept of the pH gradient
weak acids accumulate on more basic side of membrane & vice versa for bases
a coupled transport refers to:
a Secondary Active Transport carrier protein which uses an electrochemical potential difference to fuel transport
what is “controlled release” “extended release” or “sustained release”
to slow the dissolution, u can slow the absorption, in turn, prolonging the drug in the body system. Allowing for more uniform therapeutic effect while minimizing adverse effects
how does prolonging the duration of action effect the onset of action
it delays the onset
why would having a controlled/extended or sustained release be a problem
if treating someone was life-threatening where a rapid response is needed, you wouldn’t want the delayed onset of action that results from a controlled release
dissolution
for a drug to be absorbed it must 1st be dissolved in the fluid
how can you alter the rate of dissolution
coating it with wax or other water-soluble material, also complexing it with ion-exchange resins…altering the shape of drug, for example tablets dissolute slow, granules intermediate and fine particles are rapid
why is compliance easier for patients when you prolong the duration of action
patients only have to take drug twice a day vs. four, etc. (decreases frequency needed to take it)
under normal conditions how long would a drug be expected to stay in the stomach? small intestines? and Colin?
stomach: 2-4 hours, SI:4-10 and colonic tract: 12-50 hours
First-Pass Metabolism
when drug administered orally is absorbed into the blood stream and broken down by liver b4 reaching full systemic circulation
what types of factors affect bioavailability of a drug
insufficient absorption, decreased absorption, first-pass metabolism and other demographic factors (age, sex, exercise, genetics, stress, GI surgery)
what is measured by comparing the Area Under the Curve (AUC) after IV and oral administration to the plasma concentration over time
bioavailability
when the maximum (peak) plasma concentration is reached when:
drug elimination rate equals absorption rate
when does drug elimination begin
as soon as the drug enters the bloodstream
ADME stands for what referring to pharmacokinetics
Administration, Distribution, Metabolism, and Excretion
Molecular Weight
smaller passes easier, when females are lactating a larger drug would prevent it from accumulating in the breast milk
why are weak acids/bases IDEAL drugs
since they are present in both ionized and unionized forms, they can pass through lipid membranes or through water in body cause they transfer easily btw the two.
what is the bioavailability for a drug administered through an IV
100% (higher risk for adverse effects)
This type of pathway doesn’t require drug to be lipid soluble and no energy is required
paracellular pathway
what is the principle driving force for the paracellular pathway
hydrostatic pressure
why do we see a saturation point with facilitated diffusion vs. passive
only so many transporter proteins can work at one time…
why would it be wrong to give 1/5 the dose of a drug to a neonate based on the fact that they are 1/5 the weight of an adult when referring to body water
babies have more percent of body water than adults (75-80%) vs. adults 60 and elderly ~50%
acidic drugs tend to bind to plasma proteins. Describe it’s volume of distribution
Low
what is the main point to understand about perfusion rates affecting distribution…
more perfusion to the kidneys, lungs, heart, liver, and brain (Phase I) THAN the adipose, muscle, and skin (Phase II)
what are the two isoenzymes we should remember and % do they represent in Phase I of oxidation….
3A4 (50%) and 2D6 (30%)
What does Phase I of metabolism include
oxidation mainly with CYP450 (3A4) to make drug polar, able to be eliminated
Liver Disease=
Dose Adjustment!
What is a Loading Dose refer to
doubling dose may lead to a “kick start” or earlier onset of action
Define Steady-State
situation where drug in=drug out and plasma levels of drug are steady regardless of when sample is taken.
define third spacing and list examples
very little fluid exist in this space & it has no function… pleural cavity & peritoneal cavity, and GI tract
how can third-spacing lead to hypovolemia
either pt is hemorrhaging or losing fluids into one of the cavities where its not helping the body
What accounts for the decrease in % body water with increasing age
adipose tissue
How would you adjust dose for infant with more % body water
increase the dose
how would you adjust the dose for an elderly with less % body water
decrease the dose
What organs would be considered Phase I of distribution based on CO & Q
heart, lungs, liver, kidneys, and brain
what organs are considered Phase II of distribution
muscle, skin, adipose tissue
why is the measurement of volume distribution said to be “apparent”
its assumed the concentration of drug found in the sample represents all other compartments in body. Rarely true due to protein binding, ion trapping
how is volume of distribution related to drug concentration
Inversely
many acidic drugs are highly protein-bound thus would they have a small or large Vd
small
what protein are acids most likely to bind to
albumin
which type of protein are bases most likely to bind to
alpha-1 glycoprotein
also lipoproteins
what is albumin’s main funciton
maintain osmotic pressure of blood, transport endogenous substances.
this protein tranports plasma lipids & may bind drugs if albumin is saturated
lipoprotein
where are erythrocytes made
bone marrow of membranous bones-vertebrae, ribs, sternum
hemolytic anemia caused by penicillin is what type of hypersensitivity rxn
Type II, when penicillin binds to RBC, body recognizes as “foreign” launches an IgG attack
what would you see in patients with edema
dilute drugs (increase Vd) that are highly water soluble or protein bound
in capillaries what is the primary route of transportation of a drug
paracellular,
list the relative permeability of capillaries from greatest to least
liver>kidney>muscle=fetus>brain
what has a more permeable capillary bed between the muscle and the liver
the liver
list the restricted spaces of the body & why fat soluble drugs moe better across these membranes
brain, placenta, and eye; fat soluble move better across these restricted spaces b/c its dependent upon passive diffusion
what are examples of protected tissues
blood-brain barrier, placental barrier, and blood-retinal barrier
What is ion trapping
weak acidic drugs trapped in basic environments & vice versa
drugs dissolve in water (water soluble drugs) accumulate in which spaces as reservoirs
blood & interstitial fluid
how are protein-bound drugs reservoirs?
they are inactive when bound and as the same free drug is used up, then they are released
what type of reservoir can lead to toxicity
tissue protein bound drugs b/c they prolong action hence leading to harmful accumulations
what are examples of toxicity due to tissue protein bound drugs
aminoglycosides (antibiotic class), renal tissue (temporary renal failure), and central auditory tissue (deafness)
in the BBB, what cells promote formation & health of the tight junctions making drug penetration dependent on transcellular transport
astrocytes
what does inflammation do to the BBB which makes it possible to treat meningities with water soluble antibiotics
breaks down the barrier, increasing permeability
- Results of exposure to a toxic metabolite may include
cellular and tissue necrosis, anemia and blood dyscrasias, carcinogenesis, mutagenesis, teratogenesis and fetal death
phase I of drug clearance involves:
oxidation/reduction which doesn’t change water solubility, but alters property of the drug…
phase ii involves
synthetic rxns, increase polarity & water solubility. increasing drug clearance.. involve conjugation with endogenous substances (glucoronic acid, sulfate, glycine
what is the only phase II reaction occurs in the liver
glucuronidation
where is glucuronides secreted from?
the bile
what are two other substances that conjugate with amino acids in Phase II that are not secreted in bile
glutamine and glycine
what is the mechanism for acetaminophen accumulating as a toxic metabolite in the liver
it undergoes phase II preferentially (doesn’t require prior phase I oxidation) and if overdosed, overwhelms the phase II- forcing phase I metabolism.
rate of metabolism relationship with half life
inverse
what are factors affect rate of metabolism
drugs, liver disease, malaria, neoplastic disease (cancer) Age, nutritional status (protein poor-lower metabolism) vs. high protein diet speeds up) smoking & veggies speeds up. Grapefruit juice increases bioavailibiility by inhibiting intestinal elimination. intestinal microflora
factors affect glomerular filtration of a drug
MW, diseases,
describe enterohepatic recycling or recirculation
drugs with more neutral charges (greater lipid solubility) may be reabsorbed from the intestines & re-enter the liver
what pH does the urine range
4.5-8
Urine becomes more acidified in what part of the nephron
distal tubules and collecting ducts
What could you do to increase the exctretion of weak acids that in a normally acidic urine would be reabsorbed…
give them 1 to 2 mEq/kg sodium bicarbonate (alkanize) every 3-4 hrs
How could alkanizing the urine of a patient with a cocaine or aspirin overdose help them excrete them faster?
normally when the urine is acidic, this promotes the reabsorption of weak acids back to the body thus alkanizing the urine would counteract this process.
Where does active tubular reabsorption occur? What molecules is this important for? Unimportant?
Proximal tubules, important for endogenous molecules like ions, glucose, amino acids
Minimally important for most drugs
Active Tubular Secretion
runs against a concentration gradient, many drugs eliminated this way.
How will a drugs half-life be affected if it has a lower affinity for the carrier mediated tubular secretion than another drug with a higher affinity
The half life will be prolonged
in general drugs are excreted with bile when they have already undergone:
hepatic metabolism, but some may enter bile unmetabolized
drugs & metabolites present in bile are released in the gi tract via:
major duodenal papilla
what types of drugs does pulmonary excretion work on
volatile drugs that are unchanged
what are two factors affect drug excretion through breast milk
more concentration & less plasma protein binding lead to higher exretion
what is meant by the term “dosing to effect”
when condtions are present that alter 1/2 life (liver/renal ds) a physiologic marker for effectiveness or toxicity is often used to adjust dosing.
why doesn’t half life give you a good picture for full elimination
metabolites may be stored in fat cells so although it only takes 2 hours to reach t1/2, it usually takes 5X to assume total elimination
in terms of an efficacy half life, how could a drug produce an effect after its eliminated
acting intracellularly and/or remains partly bound to the receptor or is a “hit & run” that alters receptor.
What does the Cyclooxygenase enzyme do
synthesizes prostaglandins from arachidonic acid
What role does prostaglandins play
pain, inflammation, cell proliferation, mucus production, fever,
Which type of COX enzyme would be termed the “housekeeper”
COX 1, secretes mucus to protect stomach from gastric juices; clots blood, regulates perfusion to kidneys
This COX enzyme is referred to aa inducible
COX 2
COX 2 plays a role in :
inflammation site: increases prostaglandin production(macrophages & synoviocytes)
Why is COX 1 referred to as constitutive i.e. what does constitutive mean?
It is present at all times; and it has the power to form a part of something
HOw might a stomach ulcer form?
COX1 inhibitor
how can inhibiting COX2 lead to high blood P & increased CV disease risk
they are found lining interior of the bv
What role does COX2 play int he kidney, which if inhibited would lead to fluid retention
regulating water & sodium excretion
what is acetaminophen’s thought MOA
acts primarily in CNS to inhibit COX2 enzymes hence decreasing pain…. indirectly blocks…. direct effects on hypothalamus’ heat regulating center accounts for antipyretic nature
What is acetaminophens indication & dosing
it is an analgesic & antipyretic; only analgesic approved to use in infants <6 months. Dose-650-1000mg 4-6 hrs/day
What organ is most likely toxic from acetaminophen & why?
liver, normally the drug goes through Phase II metabolism here as part of the CYP450, but if it is being all used (overdose) then in can bump into Phase I producing a toxic metabolite that can accumulate in hepatocytes and destroy them.
IBuprofin causes the following ADR’s
GI (peptic ulcer disease) CV risks (stroke & MI) & kidney (high albumin binding displacing other drugs/blockage of prostaglandins regulate Q)
in addition to IBuprofin having antipyretic & analgesic properties similar to acetaminophen, what else does it function to do
anti-inflammatory
what is Ibuprofin’s MOA
it is non-selective on COX1 and COX2
why doesn’t acetaminophen have anti-inflammatory effects
Since it works in the CNS, it doesn’t inhibit COX in the peripheral tissues
What is the onset of acetaminophen
30-60 min
which drug would you choose to treat osteoarthritis with? It is less potent, and has less ADR’s
acetaminophen
Why is acetaminophen not as likely as IBuprofin to cause kidney problems
It’s protein binding is only 10-25%
What is Ibuprofins affinity to Albumin
90-99% bound
What are the 2 most important things we should know about drugs
- any drug can cause a symptom 2. any drug can cause an allergic rxn
What is the dosing for Ibuprofin
200-400 mg every 6 hours
Why is using ideal body weight in obese patients wrong for dosing?
we would underdose them because adipose tissue blocks the full effect of drugs getting to tissues
when using “adjusted body weight” they use a factor around what percent to give a medication for obese
40% (rather than using the pt weight)
Dose using “total body weight” means:
more drug for the patient who weighs more
Many carcinogens are only activated after:
biotransformation of a reactive metabolite which may cause toxic effects
What are some examples of problems caused by toxic metabolites
teratogenesis, mutagenesis, carcinogens, blood dyscrasias, tissue necrosis
How do anaerobic bacteria contribute to reabsorption in liver (enterohepatic recirculation)
they can hydrolyze the conjugated drug
The mechanism of extretion through the bile is mainly what type of transport?
carrier mediated active; transporters present in canalicular membrane of the hepatocyte
What are some examples of semi-polar solvents
alcohol & ketones (may act to induce a certain degree of polar/nonpolar)
What is cosolvency refer to:
a blending of solvents with varying degrees of polarity to create optimal polarity for solute to dissolve in solvent!
which form (ionized/unionized) would be favored in a weak acid and weak base at low pH?
HA and HB+
Would the pH be low or high when a solution is dominated by A- and HB
high or basic pH
What are some examples of tissue reservoirs
bone, GI tract, thyroid
How does meningitis make it possible for water-soluble antibiotics to cross the bbb and work to treat it
the inflammation breaks it down, makes membrane more permeable
how does ion trapping occur in fetal circulation?
Since the fetal plasma is more acidic than the mother’s weak bases accumulate across the placenta
What is the underlying cause of diabetic retinopathy
the blood ocular barrier (consists of tight junctions/nonfenestrated capillaries) becomes leaky due to inflammation & leads to eye damage
What is responsible for differences in drug metabolism in patients of varying ethnicities
*CYP450 enzyme polymorphism
What landmarks begin and end the duodenum
pylorus to suspensory ligament(Treitz ligament)
what is the mesentery’s main function
supplies blood, nerves, and lymph to the SI and GI
HOw does the Crypt of Leiberkuhn contribute to health and maintenance of SI
consist of undifferentiated cells to replace epithelium
