Chapter 52 - Pharmaceutical considerations for neuro

Question 1

Why are CNS drug concentrations often lower than plasma concentrations after systemic administration?
A. Because of multiple barriers that prevent foreign materials from entering the CNS.
B. Due to faster metabolism in the CNS than in the plasma.
C. Because the CNS selectively expels therapeutic drugs.
D. Due to higher enzymatic activity in the CNS.

Answer 1

A. Because of multiple barriers that prevent foreign materials from entering the CNS.

Question 2

What purpose do the barriers like the BBB serve in the CNS?

Answer 2

They protect the CNS from foreign materials and maintain a constant environment.

Question 3

What are the three barriers collectively referred to as the BBB?

Answer 3

Blood-brain barrier,
blood-spinal cord barrier,
and blood-cerebrospinal fluid barrier.

Question 4

Approximately what percentage of potential therapeutic drugs does the BBB prevent from entering the CNS?
A. 50%
B. 75%
C. 98%
D. 100%

Answer 4

C. 98%

Question 5

What is the primary role of brain microvascular endothelial cells (BMVEC) in the BBB?

Answer 5

They limit transport across the BBB due to their specialized structure.

Question 6

What are the primary components of the BBB’s physical barrier?

Answer 6

Tight junctions and integral membrane proteins like claudins and occludin

Question 7

Besides a physical barrier, what other function does the BBB serve?

Answer 7

It acts as a metabolic barrier with drug-metabolizing enzymes.

Question 8

What can result from the active transport systems across the BBB?

Answer 8

Both uptake of substances into the CNS and efflux of drugs from the CNS.

Question 9

What kind of molecules do carrier-mediated transport mechanisms carry across the BBB?

Answer 9

Only small molecules like glucose and amino acids.

Question 10

How do drug efflux transporters protect the CNS?

Answer 10

By limiting the entry of neurotoxins and therapeutic drugs into the brain.

Question 11

What mechanism is described that allows certain drugs to gain access to the CNS?

Answer 11

Carrier-mediated transport

Question 12

What role do drug efflux transporters play in relation to the CNS?

Answer 12

They limit drug entry and may contribute to pharmacoresistance

Question 13

Why is lipophilicity an important characteristic for CNS drug permeability?

Answer 13

It is required for the drug to pass through epithelial cell membranes

Question 14

What is a disadvantage of high lipophilicity in drugs?

Answer 14

It often results in rapid metabolic turnover and poor absorption

Question 15

What molecular weight is proposed as a cutoff for passive brain permeability of drugs?
A. Less than 200 Da
B. Less than 450 Da
C. Less than 1000 Da
D. Less than 1500 Da

Answer 15

B. Less than 450 Da

Question 15

How does the pKa of a drug influence its ability to cross biologic membranes like the BBB?
A. Drugs with pKa values between 4.0 and 10.0 are ideal for permeating the BBB
B. Only drugs with pKa values above 10 can cross the BBB
C. pKa has no influence on a drug’s ability to cross the BBB
D. Lower pKa values indicate higher permeability across the BBB

Answer 15

A. Drugs with pKa values between 4.0 and 10.0 are ideal for permeating the BBB

Question 16

Why is hydrogen bonding capacity significant for drug permeation across the BBB?
A. It increases the drug’s solubility in blood
B. It enhances membrane permeation efficiency
C. It decreases membrane permeation and may indicate P-glycoprotein substrate affinity
D. It is only relevant for drug design, not for permeation

Answer 16

C. It decreases membrane permeation and may indicate P-glycoprotein substrate affinity

Question 17

What characteristic of drugs is often used as a surrogate measure of hydrogen bonding capacity?
A. Molecular weight
B. Lipophilicity
C. Polar surface area (PSA)
D. pKa

Answer 17

C. Polar surface area (PSA)

Question 18

What effect does a higher Polar Surface Area (PSA) have on a drug’s ability to cross the BBB?
A. It has no effect
B. It increases permeability
C. It leads to higher toxicity
D. It usually results in decreased permeability

Answer 18

D. It usually results in decreased permeability

Question 19

what is the typical impact of protein binding on drug concentrations within the CNS?
A. It is the major determinant
B. It has a moderate effect
C. It has a minimal role
D. It is the only factor considered

Answer 19

C. It has a minimal role

Question 20

What Log P value is considered optimal for CNS activity of drugs?
A. 0.5
B. 1.0
C. 2.9
D. 5.0

Answer 20

C. 2.9

Question 21

What happens to drugs with a Log P of greater than 5?
A. They are absorbed more efficiently
B. They may not be absorbed due to membrane trapping
C. They become highly soluble in water
D. They do not cross the BBB at all

Answer 21

B. They may not be absorbed due to membrane trapping

Question 22

In areas without protective barrier membranes, what determines drug concentrations in the interstitial fluid (ISF)?

Answer 22

Plasma protein binding

Question 23

What is a known inducer of P-glycoprotein that could lower drug concentrations in the CNS?

Answer 23

Rifampin

Question 24

Which age groups in animals have different BBB permeability compared to adult animals?

Answer 24

Both neonatal and geriatric

Question 25

In young animals, what may explain an increased tendency for drug toxicity?
A. Higher plasma protein concentration
B. Decreased myelination
C. Increased P-glycoprotein expression
D. Enhanced drug metabolism

Answer 25

B. Decreased myelination

Question 26

What may result in increased drug permeability to the CNS in neonatal animals?
A. Increased myelination
B. Limited P-glycoprotein expression
C. Higher plasma protein concentration
D. Decreased fluid volume

Answer 26

B. Limited P-glycoprotein expression

Question 27

How can diseases causing CNS inflammation affect the BBB?
A. By decreasing drug permeability
B. By leading to decreased drug permeability in chronic phases
C. By increasing drug permeability
D. They have no effect on the BBB

Answer 27

C. By increasing drug permeability

Question 28

What is a common result of the initial phase of BBB disruption in disease states?
A. Permanent closure of the BBBB. Reversible disruption
C. Immediate neuronal death
D. Long-term enhancement of BBB function

Answer 28

B. Reversible disruption

Question 29

Which enzymes are involved in the breakdown of the BBB’s tight junctions?
A. Matrix metalloproteinase 2
B. COX-2
C. Lipases
D. Both A and B

Answer 29

D. Both A and B

Question 30

What is the outcome of the second, more severe phase of BBB disruption in disease?

Answer 30

Vasogenic edema and hemorrhage

Question 31

In septic meningitis, what effect do proinflammatory cytokines have on the BBB?

Answer 31

They open BBB intercellular tight junctions

Question 32

What percentage of meningitis/meningoencephalitis cases in horses was thought to be due to trauma?
A. 10%
B. 32%
C. 50%
D. 75%

Answer 32

B. 32%

Question 33

What factor is associated with increased CSF drug concentrations during septic meningitis?
A. Reduced CSF outflow resistance
B. Decreased production of CSF
C. Inhibition of P-glycoprotein
D. All of the above

Answer 33

C. Inhibition of P-glycoprotein

Question 34

What factor does NOT necessarily increase the efficacy of drugs in the CSF during CNS infections?
A) Increase in drug concentration
B) Decrease in protein concentration
C) Increase in lipophilicity
D) Decrease in inflammation

Answer 34

D) Decrease in inflammation

Question 35

Which property is NOT listed as desirable for antimicrobials treating CNS infections?
A) High protein binding
B) Low number of hydrogen bonds
C) High lipophilicity
D) pKa between 4 and 10

Answer 35

A) High protein binding

Question 36

What is used as an indicator of drug penetration into the CNS in studies?
A) CSF:pH ratio
B) CSF:serum ratio
C) Serum:lipophilicity index
D) CSF:protein concentration

Answer 36

B) CSF:serum ratio

Question 37

Which class of drugs was found to have better penetration into the CSF of normal horses?
A) Fluoroquinolones
B) β-lactam antibiotics
C) Aminoglycosides
D) First-generation cephalosporins

Answer 37

A) Fluoroquinolones

Question 38

Why may the usefulness of certain drugs be limited despite their permeation into the CSF?
A) High cost
B) Resistance and/or limited spectrum of activity
C) High protein binding
D) Low lipophilicity

Answer 38

B) Resistance and/or limited spectrum of activity

Question 39

Which type of drugs tends to persist for longer periods in the CSF than in the plasma?
A) Hydrophilic drugs
B) Lipophilic drugs
C) β-lactam antibiotics
D) Aminoglycosides

Answer 39

B) Lipophilic drugs

Question 40

For which generation of cephalosporins is permeation into the CSF less likely?
A) Third-generation
B) Fourth-generation
C) First- and second-generation
D) All generations equally

Answer 40

C) First- and second-generation

Question 41

What adjustment might be necessary for drugs with low CSF penetration to achieve a therapeutic effect?
A) Lower doses and less frequent dosing
B) Higher doses and/or more frequent dosing intervals
C) Switching to oral administration
D) Combination with aminoglycosides

Answer 41

B) Higher doses and/or more frequent dosing intervals

Question 42

Which drug reaches minimal to undetectable concentrations in the CSF of healthy adult horses?
A) Enrofloxacin
B) Amikacin
C) Metronidazole
D) Chloramphenicol

Answer 42

B) Amikacin

Question 43

What is a significant risk when trying to increase the dose of aminoglycosides to achieve therapeutic CSF concentrations?
A) Hyperlipidemia
B) Severe nephrotoxicity
C) Hepatotoxicity
D) Neurotoxicity

Answer 43

B) Severe nephrotoxicity