Pharmcology - lecture 2 Flashcards
What is pharmacokinetics?
time course of drug action
- as it relates to concentration of drug in plasma (how body deals with a drug)
How is bioavailability for enteral and parenteral routes different?
Enteral (GI) = F
What is the equation for AUC?
What are the two ways to use AUC?
AUC = Dose/ Conentration
or
AUC = DOSE/ (C/F)
- Determine bioavailability
- Used to compare amount of drug that reaches the systemic circulation by different routes of administration - Compare clearance of a drug in different individuals given the same dose (CL)
What is first pass metabolism?
First pass metabolism
- all drugs absorbed by oral administration through intestines pass first through LIVER before they reach the heart & are redistributed in body
The following describes what type of drug passage:
- small molecules (
Aqeuous
The following describes what type of drug passage:
passive process
driven by concentration gradient
the rate of absorption increases with increasing drug concentration
Lipid diffusion
- the more lipid-soluble the faster the rate of transport
lipid-soluble drugs cross membranes readily, but may be poorly soluble in aqueous gut fluids, which may limit their absorption.
(If TOO lipid soluble = will precipitate in the small intestine and may not be absorbed at all)
_ionized/non-ionized____ form of drug is less soluble
Portioned forms of (acid/base) are more lipid soluble.
ionized form
- Ionization state depends on pH of environment and pKa of the drug
- determines lipid solubility
ACID is more soluble!
Acids = protonated form is uncharged
( non- ionized = more lipid soluble)
Bases = protonated form is CHARGED –> ionized (less lipid soluble)
The percent of ionization is equal for a weak acid and weak base where?
Where do weak bases get concentrated? Weak acids?
Small intestine
- pH of about 6
weak bases more ionized in acidic environments –> like the stomach therefore they are LESS readily absorbed
(weak acid = readily absorbed in acidic environment of stomach)
BUT both weak acids (pKa of drug) and weak bases are more readily absorbed in the small intestine (due to larger SA and pH)
What is ion trapping?
Non-ionized forms of a weak acid or a weak base can diffuse across lipid membranes & equilibrate between blood & urine
- fraction of ionized drug will be established in each compartment based on difference between compartmental pH and drug pKa
IONIZED forms of a drug can become trapped resulting in greater concentrations in compartments where the ionized form is favored
(weak acids more concentrated in alkaline compartments, vice versa for weak base)
Rate of drug absorption across membranes is directly proportional to the available surface area,
therefore The_______ is the main site for absorption of most orally administered drugs because it has a much larger surface area than the stomach.
small intestine
What is first pass effect?
What is enterohepatic circulation?
First-pass effect: some drugs are highly metabolized when they pass through the liver—only a fraction (F) of the absorbed drug reaches the systemic circulation (F = (oral)bioavailability).
- Intestine or 2. Liver
Enterohepatic circulation: drugs may be secreted into the bile and reabsorbed via the intestine. This can delay delivery to the systemic circulation and may reduce bioavailability.
(further limit bioavailability)
**stomach contents (food) and gastric emptying time can affect the rates of drug absorption longer drug stays in stomach = LESS ABSORPTION ***
What is bioavailability?
Why would a drug have less than 100% bioavailability?
The fraction (F) of the administered dose that reaches the systemic circulation in its active form.
A drug may have less than 100% bioavailability if it is
a) incompletely absorbed or
b) if it undergoes metabolism, e.g. while going through the liver via the portal circulation (first-pass metabolism).
F = AUC(oral)/AUC (iv)
What is the following called (and describe what it means):
cases a drug may be prepared in a formulation that provides a fraction of the total weight of drug as active drug and the remainder as an inactive salt.
example?
SALT FACTOR
- The fraction of total drug that will be delivered as active drug to the systemic circulation is the SALT FACTOR
3. Aminophylline
1 gram of aminophylline contains 0.8g of the active drug (theophylline) and 0.2g of salt.
What is the salt factor?
What must be adjusted?
- 8
- dose must be adjusted by salt factor to achieve target concentration of active drug
Loading dose = Vd * TC/ F*S
What is the benefit of sublingual drug admin?
The benefit of rectal?
What specific cases?
- by-passes portal circulation and therefore avoids first pass metabolism.
- higher pH may be beneficial for absorption of more basic drugs. (more alkaline= basic drugs better absorbed)
. Rectal
Advantages:
~50-60% of absorbed drug by-passes portal circulation and therefore avoids first pass metabolism.
useful in cases of nausea and vomiting**
How are inhaled drugs absorbed? What type of diffusion?
What type of diffusion drives transdermal drug admin?
passive diffusion
concentration gradient
Where is parenteral drug admin fastest?
What is the most risky disadvantage of intravenous parenteral administration?
in highly vascularized tissues such as skeletal muscle
“BOLUS EFFECT”
Where do drugs usually get distributed first?(3)
What factors influence distribution?
- Brain
- Heart
- Kidney
- Blood flow
- tissue mass
- transport mechanism
- permeability characteristics
- ION TRAPPING
- local pH differences can result in relative concentration of drugs in different compartments pr - PROTEIN BINDING
- only unbound drug distributes to tissues
Albumin binds to ____ drugs
Alpha acid glycoprotein binds ____ drugs
- acidic
2. Basic
Define one compartment vs. two compartment distribution
One-compartment: a rapid equilibrium is achieved between plasma and tissue distribution following drug administration.
Plasma concentration-time profile declines mono-exponentially.
Two-compartment: rapid distribution to a central compartment (plasma) is followed by slow distribution to other tissues/binding sites (second compartment).
This results in a bi-exponential plasma concentration-time profile.
What is volume of distribution?
A measure of how evenly distributed a drug is in the body.
Vd is the theoretical volume of fluid into which the total drug administered would have to be diluted to produce the concentration in plasma.
V=D/C
The antibiotic tobramycin is given to a patient with gram-negative bacteremia. The patient weight is 60 kg and the patient receives a loading dose of 1.5 mg/kg (90 mg total). If the initial plasma concentration of tobramycin is 6 mg/liter after intravenous dosing, what is the apparent volume of distribution (Vd) for this drug?
B) 15 L
Theophylline is given to a patient with bronchial asthma in the emergency room. The target plasma level is 10 mg/ml and the patient weighs 50 kg. The average volume of distribution for theophylline is 0.5 liters/kg. Which of the following is the correct loading dose?
250 mg
0.5 L / kg (v of D) * 50 = 25 L
25 L * 10 ug/mL or 10 mg/L = 250 mg
An increase in the unbound fraction of total [drug] (e.g. in hypoalbuminemia) will result in an increase in the apparent ______
volume of distribution (Vd).
For example, consider a drug that is 90% bound to plasma albumin (10% unbound in the plasma). If the volume of distribution under these conditions is 14L, assuming no other parameters change, a drop in plasma [albumin] that decreases the fraction of bound drug to 80% (20% unbound in plasma) will increase Vd to ≈____
24L
What are the major compartments of drug distribution?
—plasma (5% of body weight) —interstitial fluid (16%) —intracellular fluid (35%) —transcellular fluid (2%) synovial, ocular fluid —fat (20%).
Lipid-insoluble drugs are mainly confined to ____ and _____; most do not enter the brain following acute dosing.
Lipid-soluble drugs reach all compartments, and may accumulate in ____.
For drugs that accumulate outside the plasma compartment, Vd may exceed____.
- plasma
- interstitial fluids
- fat
- total body volume
(if accumulates in fat)
What are drug reservoirs?
What are 2 in particular?
What can also serve as a drug reservoir?
What can increase the proportion of an unbound drug and result in greater distribution?
Drug distribution is not uniform
Fat and muscle in particular can act as drug reservoirs.
More drug may be stored in these tissues than remains in the systemic circulation.
Gradual release of drug from these sites can prolong the therapeutic effect or result in toxicity.
Plasma proteins can also serve as a drug reservoir.
Sulfonamides may compete for protein binding and increase the unbound fraction of other drugs.
Sulfanamide can increase proportion of unbound drug and result in greater distribution of unbound drug
