drugz

Question 1

A 65-yr woman, who was on thrice-weekly hemodialysis for chronic renal failure presented to her family physician with a painful rash on her abdomen. This was vesicular in nature, extending across the left T10 dermatome, and was diagnosed as herpes zoster. She was prescribed oral acyclovir, which is an antiviral medication (MW=225 Da, pKa=2.1(N1) & 9.25(N7), bioavailability= 10-20%). Which organs likely dictate its low bioavailability?

Stomach and kidney
Stomach and Intestine
Intestine and liver
liver and kidney

Answer 1

Intestine and liver.

Bioavailability is determined by the degrees of absorption (GI tract) and the first pass metabolism (liver).

Question 2

Bioavailability

Answer 2

A measure of the drug available to the systemic circulation over time after administration (usually oral).

Question 3

Routes of drug excretion

Answer 3

renal excretion (glomerular filtration, active tubular secretion, and passive tubular reabsorption, can be controlled by adjusting urine pH)
biliary excretion

Question 4

By alkalinizing the urine to pH 7.9 with systemic administration of sodium bicarbonate, the clearance of which of the following two barbiturates (weak acids) can be more effectively enhanced?

Phenobarbital (pKa=7.2)
Barbital (pKa=7.9)

Answer 4

Phenobarbital.

At pH 7.9, which matches the pKa of barbital, ionized barbital : nonionized barbital = 1 : 1

At pH 7.9, which is above the pKa of phenobarbital (7.2), there is more phenobarbital in its ionized form than non-ionized. This will slow down renal reabsorption and encourage renal clearance.
Note: the students don’t actually have to calculate the actual ratio of ionized and nonionized phenobarbital at pH 7.9 to appreciate that it should above 1.

Question 5

Drugs in their _______ form cannot be effectively reabsorbed

Answer 5

ionized

Question 6

Weak Acid

Answer 6

HA –> A- + H+

decrease pH (increase [H+]), you will shift left and weak acid will be mostly non-ionized. Decrease 1pH, get 10 fold increase in non-ionized form of weak acid – more likely to be reabsorbed. Most drugs absorbed in the stomach (low pH) are weak acids. Makes sense!

Question 7

Weak base

Answer 7

B + H+ –> BH+

Question 8

Henderson-Hasselbalch Equation

Answer 8

pKa = pH + long [protonated]/[nonprotonated]

*pKa = pH + P/UP

Question 9

What is the upper limit to the volume of distribution? (Vd)

Answer 9

infinite.

Question 10

Volume of distribution

Answer 10

relates the amount of drug in the body to the plasma concentration

Vd = amount of drug in the body / [drug] in plasma

**more in plasma = not being taken up into tissues, so low volume of distribution

Question 11

How can we estimate how much drug is left in the body after a period of time?

Answer 11

The only effective way of estimating the amount of drug in the body is to draw blood and measure plasma drug concentration

Question 12

Why do we need the term “volume of distribution”?

Answer 12

Volume of distribution literally allows us to relate the amount of drug in the body to the plasma drug concentration.

Question 13

What are the major three families of Cytochrome P450 enzymes?

Answer 13

CYP 1-3

Question 14

The patient’s enhanced risk of bleeding is in fact due to genetic variations. DNA typing reveals that the patient is a CYP2C9 2/3 carrier and a VKORC1 (-1639 G>A) A/A double carrier. What is a CYP2C9 2/3 genotype?

a) Two copies of CYP2C9 each with a distinct SNP variant allele
b) Defective gene splicing between exon 2 and 3
c) Nucleotide base insertions between the second and third codon of CYP2C9
d) CYP2C9 with two premature stop codons
A total of five CYP2C9 repeats polymorphism

Answer 14

Two copies of CYP2C9 each with a distinct SNP variant allele

Question 15

What happens to an acidic drug in an acidic medium (think stomach).

Answer 15

In acidic medium, lots of protons are present shifting equilibrium equation to the left favoring non-ionized HA. Thus in acidic medium acidic drug is present more in unionized form, which increases its absorption. This is why acidic drugs are better absorbed from the stomach.

Question 16

Modes of drug permeation

Answer 16

(solubility*surface area) / thickness

thick skin vs. behind ear, lower back, etic.

Question 17

What pumps drugs out of cells?

Answer 17

p-glycoprotein (efflux pump),

for example, kicks things out of CNS

Question 18

Tell me about metabolism phase I

Answer 18

uses cytochrome P450 enzymes

convert a parent drug to more polar (water soluble) active metabolites by unmasking or inserting a polar functional group (-OH, -SH, -NH2)

• decreased phase I metabolism means drugs with longer half-lives
• pro-drugs by themselves aren’t active (maybe because active drug is not absorbed as well, take advantage of P450 metabolism to make active in the body)

Question 19

Major human liver P450s

Answer 19

CYP2CR, CYP2D6, CYP3A4

Question 20

What is the opposite of renal absorption?

Answer 20

Renal clearance.

Non-ionized for renal absorption, ionized for renal clearance

Question 21

steady state

Answer 21

the condition where the averaged plasma drug concentration does not change (4-5 half lives), same whether you give it oral, IV constant vs. bolus perfusion,
applies to first-order kinetics

Question 22

maintenance dose

Answer 22

at steady state, the maintenance dosing rate must be equal to the rate of elimination

maintenance dosing rate = CL * Cp

Cp= is the target plasma [drug]

Question 23

first order drug elimination

Answer 23

drug administration = drug elimination

has a half-life which can help determine drug dosing etc.

majority of drug relationships you see in the clinic

first-order can appear like zero-order : overdose drug — saturate ability to metabolize and thus concentration will grow more with dose (deviation for normal angled line graph)

Question 24

zero order drug elimination

Answer 24

concentration increased disproportionately to dose

think of a fire hose into a sink! can’t drain aat the rate it is coming in.

Question 25

clearance

Answer 25

clearance of a drug is a measure of the efficiency of irreversible removal of a drug by an eliminating organ
dependent on the drug and the condition of the eliminating organ

*susceptible to change due to kidney disease or hepatic disease

Question 26

Half life

Answer 26

(0.693*Vd) / (CL)

time it takes for concentration of drug to drop by half, dependent on Vd and CL
doesn’t change with first-order kinetics (independent of concentration)

Question 27

A drug is lipid-solubilized and is taken up into the body’s tissues more readily. What would you expect of the Vd?

Answer 27

It would increase. The amount of drug in the body > [drug] in plasma.

Question 28

Compare zero-order to first-order elimination

Answer 28

Zero-order = elimination rate is constant and elimination process is saturated

First-order = elimination rate is proportional to drug plasma concentration and has a characteristic half-life.

*most drugs are eliminated with first-order kinetics

Question 29

Loading dose

Answer 29

Vd * Cp

Question 30

maintenance dosing rate

Answer 30

CL * Cp

IV infusion: dosing rate = infusion rate

Intermittent dose: dosing rate = maintenance dose / dose interval

Oral dose: dosing rate (oral) = dosing rate /bioavailability

Question 31

Phase II metabolism

Answer 31

“conjugation reactions” that increase water solubility of drug with a polar moiety

favor excretion

convert a parent drug to more polar (water soluble) inactive metabolites by conjugation of subgroups to -OH, -SH, -NH2 functional groups on drug

drugs metabolized via phase II reactions are renally excreted

Question 32

You are trying to determine drug dosing for a patient who has renal disease. How may their dosing rate compare to the rate of patient’s without renal disease?

Answer 32

Assumption: renal disease will decrease the body’s ability to clear the drug aka CL decrease. And by equation dosing rate = CL * Cp, lower CL would mean lower dosing rate.

Question 33

A patient’s ability to absorb drug from their blood is impaired. How does this affect loading dose?

Answer 33

Low absorption = high plasma drug concentration. Loading dose = Vd * Cp, so loading dose would increase.

Question 34

You are trying to determine a drug therapy plan for a patient who has renal disease. What factor(s) of drug metabolism would renal disease largely affect?

Answer 34

Clearance! Decreased renal function would decrease clearance. This would increase the half life of the drug. It would also decrease your dosing rate. Both make sense as lower clearance = more in body longer.

Question 35

enzyme inhibition

Answer 35

The increased degradation and decreased expression (transcription or translation) of P450. Usually as a result of another molecule triggering the event.

Question 36

inhibition of p-glycoprotein

Answer 36

toxic level of drug in the system

*p-glycoprotein transfers drug to the bile or lumen

Question 37

enzyme induction?

Answer 37

Increased expression of cytochrome P450, usually as a result of another molecule triggering the event

Question 38

Ampicillin is eliminated by first-order kinetics. Which of the following statements best describes the process by which the plasma concentration of this drug declines?

(A) There is only 1 metabolic path for drug elimination

(B) The half-life is the same regardless of the plasma concentration

(C) The drug is largely metabolized in the liver after oral administration and has low bioavailability

(D) The rate of elimination is proportional to the rate of administration at all times

(E) The drug is distributed to only 1 compartment outside the vascular system

Answer 38

“First-order” means that the elimination rate is proportional to the concentration perfusing the organ of elimination. The half-life is a constant. The rate of elimination is proportional to the rate of administration only at steady state. The order of elimination is independent of the number of compartments into which a drug distributes. The answer is B.

Question 39

A 12-year-old child has bacterial pharyngitis and is to receive an oral antibiotic. She complains of a sore throat and pain on swallowing. The tympanic membranes are slightly reddened bilaterally, but she does not complain of earache. Blood pressure is 105/70 mm Hg, heart rate 100/mm, temperature 37.8 °C (100.1 °F). Ampicillin is a weak organic acid with a pKa of 2.5. What percentage of a given dose will be in the lipid-soluble form in the duodenum at a pH of 4.5?

(A) About 1%

(B) About 10%

(C) About 50%

(D) About 90%

(E) About 99%

Answer 39

Ampicillin is an acid, so it is more ionized at alkaline pH and less ionized at acidic pH. The Henderson-Hasselbalch equation predicts that the ratio changes from 50/50 at the pH equal to the pKa to 1/10 (protonated/unprotonated) at 1 pH unit more alkaline than the pKa and 1/100 at 2 pH units more alkaline. For acids, the protonated form is the nonionized, more lipid-soluble form. The answer is A.

Question 40

Botulinum toxin is a large protein molecule. Its action on cholinergic transmission depends on an intracellular action within nerve endings. Which one of the following processes is best suited for permeation of very large protein molecules into cells?

(A) Aqueous diffusion

(B) Endocytosis

(C) First-pass effect

(D) Lipid diffusion

(E) Special carrier transport

Answer 40

Endocytosis is an important mechanism for transport of very large molecules across membranes. Aqueous diffusion is not involved in transport across the lipid barrier of cell membranes. Lipid diffusion and special carrier transport are common for smaller molecules. The first-pass effect has nothing to do with the mechanisms of permeation; rather, it denotes drug metabolism or excretion before absorption into the systemic circulation. The answer is B.

Question 41

A 3-year-old is brought to the emergency department having just ingested a large overdose of tolbutamide, an oral antidiabetic drug. Tolbutamide is a weak acid with a pKa of 5.3. It is capable of entering most tissues, including the brain. On physical examination, the heart rate is 100/min, blood pressure 90/50 mm Hg, and respiratory rate 20/min. Which of the following statements about this case of tolbutamide overdose is most correct?

(A) Urinary excretion would be accelerated by administration of NH4Cl, an acidifying agent

(B) Urinary excretion would be accelerated by giving NaHCO3, an alkalinizing agent

(C) Less of the drug would be ionized at blood pH than at stomach pH

(D) Absorption of the drug would be slower from the stomach than from the small intestine

(E) Hemodialysis is the only effective therapy

Answer 41

Questions that deal with acid-base (Henderson-Hasselbalch) manipulations are common on examinations. Since absorption involves permeation across lipid membranes, we can in theory treat an overdose by decreasing absorption from the gut and reabsorption from the tubular urine by making the drug less lipid-soluble. Ionization attracts water molecules and decreases lipid solubility. Tolbutamide is a weak acid, which means that it is less ionized when protonated, ie, at acid pH. Choice C suggests that the drug would be less ionized at pH 7.4 than at pH 2.0, which is clearly wrong for weak acids. Choice D says (in effect) that the more ionized form is absorbed faster, which is incorrect. A and B are opposites because NH4Cl is an acidifying salt and sodium bicarbonate an alkalinizing one. (From the point of view of test strategy, opposites in a list of answers always deserve careful attention.) E is a distracter. Because an alkaline environment favors ionization of a weak acid, we should give bicarbonate. The answer is B. Note that clinical management of overdose involves many other considerations in addition to trapping the drug in urine; manipulation of urine pH may be contraindicated for other reasons.

Question 42

The pharmacokinetics of a new drug are under study in a phase 1 clinical trial. Which statement about the distribution of drugs to specific tissues is most correct?

(A) Distribution to an organ is independent of blood flow

(B) Distribution is independent of the solubility of the drug in that tissue

(C) Distribution into a tissue depends on the unbound drug concentration gradient between blood and the tissue

(D) Distribution is increased for drugs that are strongly bound to plasma proteins

(E) Distribution has no effect on the half-life of the drug

Answer 42

This is a straightforward question of pharmacokinetic distribution concepts. From the list of determinants of drug distribution given on page 6, choice C is correct.

Question 43

The pharmacokinetic process or property that distinguishes the elimination of ethanol and high doses of phenytoin and aspirin from the elimination of most other drugs is called

(A) Distribution

(B) Excretion

(C) First-pass effect

(D) First-order elimination

(E) Zero-order elimination

Answer 43

The excretion of most drugs follows first-order kinetics. However, ethanol and, in higher doses, aspirin and phenytoin follow zero-order kinetics; that is, their elimination rates are constant regardless of blood concentration. The answer is E.