Pharmcology - lecture 2

Question 1

What is pharmacokinetics?

Answer 1

time course of drug action

- as it relates to concentration of drug in plasma (how body deals with a drug)

Question 2

How is bioavailability for enteral and parenteral routes different?

Answer 2

Enteral (GI) = F

Question 3

What is the equation for AUC?

What are the two ways to use AUC?

Answer 3

AUC = Dose/ Conentration

or

AUC = DOSE/ (C/F)

1. Determine bioavailability
   - Used to compare amount of drug that reaches the systemic circulation by different routes of administration
2. Compare clearance of a drug in different individuals given the same dose (CL)

Question 4

What is first pass metabolism?

Answer 4

First pass metabolism
- all drugs absorbed by oral administration through intestines pass first through LIVER before they reach the heart & are redistributed in body

Question 5

The following describes what type of drug passage:

1. small molecules (

Answer 5

Aqeuous

Question 6

The following describes what type of drug passage:

passive process

driven by concentration gradient

the rate of absorption increases with increasing drug concentration

Answer 6

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)

Question 7

_ionized/non-ionized____ form of drug is less soluble

Portioned forms of (acid/base) are more lipid soluble.

Answer 7

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)

Question 8

The percent of ionization is equal for a weak acid and weak base where?

Where do weak bases get concentrated? Weak acids?

Answer 8

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)

Question 9

What is ion trapping?

Answer 9

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)

Question 10

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.

Answer 10

small intestine

Question 11

What is first pass effect?

What is enterohepatic circulation?

Answer 11

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).

1. 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 ***

Question 12

What is bioavailability?

Why would a drug have less than 100% bioavailability?

Answer 12

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)

Question 13

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?

Answer 13

SALT FACTOR

• The fraction of total drug that will be delivered as active drug to the systemic circulation is the SALT FACTOR
  3. Aminophylline

Question 14

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?

Answer 14

0. 8
   - dose must be adjusted by salt factor to achieve target concentration of active drug

Loading dose = Vd * TC/ F*S

Question 15

What is the benefit of sublingual drug admin?

The benefit of rectal?
What specific cases?

Answer 15

1. by-passes portal circulation and therefore avoids first pass metabolism.
2. 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**

Question 16

How are inhaled drugs absorbed? What type of diffusion?

What type of diffusion drives transdermal drug admin?

Answer 16

passive diffusion

concentration gradient

Question 17

Where is parenteral drug admin fastest?

What is the most risky disadvantage of intravenous parenteral administration?

Answer 17

in highly vascularized tissues such as skeletal muscle

“BOLUS EFFECT”

Question 18

Where do drugs usually get distributed first?(3)

What factors influence distribution?

Answer 18

1. Brain
2. Heart
3. Kidney
4. Blood flow
5. tissue mass
6. transport mechanism
7. permeability characteristics
8. ION TRAPPING
   - local pH differences can result in relative concentration of drugs in different compartments pr
9. PROTEIN BINDING
   - only unbound drug distributes to tissues

Question 19

Albumin binds to ____ drugs

Alpha acid glycoprotein binds ____ drugs

Answer 19

1. acidic

2. Basic

Question 20

Define one compartment vs. two compartment distribution

Answer 20

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.

Question 21

What is volume of distribution?

Answer 21

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

Question 22

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?

Answer 22

B) 15 L

Question 23

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?

Answer 23

250 mg

0.5 L / kg (v of D) * 50 = 25 L

25 L * 10 ug/mL or 10 mg/L = 250 mg

Question 24

An increase in the unbound fraction of total [drug] (e.g. in hypoalbuminemia) will result in an increase in the apparent ______

Answer 24

volume of distribution (Vd).

Question 25

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 ≈____

Answer 25

24L

Question 26

What are the major compartments of drug distribution?

Answer 26

—plasma (5% of body weight)
—interstitial fluid (16%)
—intracellular fluid (35%)
—transcellular fluid (2%)  synovial, ocular fluid 
—fat (20%).

Question 27

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____.

Answer 27

1. plasma
2. interstitial fluids
3. fat
4. total body volume
   (if accumulates in fat)

Question 28

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?

Answer 28

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