Module 2

Question 1

Make a list of possible reasons that oral administration of a drug might be unsatisfactory or at least have decreased bioavailability and give examples. You should be able to come up with at least 5 answers

Answer 1

• instability in stomach acid
  
  • degraded by pancreatic enzymes (proteins such as insulin)
  • insolubility (ketoconazole in patients on a proton pump inhibitor)
  • metabolized by gut bacteria
  • poor absorption because of permanent charge or high degree of hydrogen bonding to water (quaternary amines such as neostigmine)
  • high first pass metabolism (nitroglycerine)
  • substrate for transporter that pumps the drug back into the gut lumen (digoxin but oral bioavailability still sufficient)
  • need for rapid response (epinephrine for anaphylaxis)
  • need to make sure of therapeutic drug level because of a potentially fatal disease (antibiotics for subacute bacterial endocarditis)

Question 2

The pKa of diazepam is 3.4. If you did not know the structure of diazepam, what does the pKa of 3.4 indicate?

Answer 2

A pKa of 3.4 indicates a strong acid or a weak base. Without knowing the structure it is not possible to tell which it is. Any acid has a conjugate base and any base has a conjugate acid

Question 3

Paramedics and most other health care professionals are not permitted to give drugs intravenously mostly because

Answer 3

The effects of IV drugs are much greater than when the same drug is given orally and can be lethal. This is because very high concentrations are produced and there is little time for redistribution of the drug to tissues such as fat

Question 4

Which of the following characteristics would prevent a drug from being well absorbed from the intestine?

Answer 4

Being 100% ionized at pH 7 (i.e. quaternary amine) AND having many functional groups that are ionized or can hydrogen bond to water

Question 5

What determines the Tmax (i.e. the time to maximal serum concentration) after oral administration

Answer 5

gastric emptying. To the first approximation, nothing is absorbed from the stomach. Even alcohol, which has a very high membrane permeability is affected by gastric emptying. Therefore, if you drink alcohol on an empty stomach the Tmax is significantly shorter and Cmax is significantly higher than if you drink alcohol after eating a fatty meal which delays gastric emptying. The usual Tmax for drugs taken on an empty stomach is about 1 hour

Question 6

How does drug solubility affect oral bioavailability?

Answer 6

a drug cannot be absorbed unless it is in solution. The solubility does not have to be high because of the relatively long transit time in the intestine, but there still has to be a reasonable degree of water solubility

Question 7

How might proton pump inhibitors affect oral bioavailability?

Answer 7

A charge markedly increases water solubility. Many drugs are basic, but require an acidic environment in which they become positively charged. Of the oral drugs that have been approved recently more than 50% have significantly decreased oral bioavailability in patients on proton pump inhibitors.

Question 8

Provide three reasons why a sublingual formulation would be an advantage over a swallowed formulation

Answer 8

• More rapid absorption because it does not depend on gastric emptying, which is important for something like nitroglycerine
  
  • Not affected by nausea and vomiting such as in the treatment of migraine headaches
    Eliminates first pass metabolic clearance and instability in the GI tract, again an issue for nitroglycerine

Question 9

A past version of the UofT pharmacology textbook says “ionizable drugs can enter the CNS only if they have appropriate transporters”. Is that correct?

Answer 9

Almost all drugs of abuse and CNS active drugs such as antidepressants and antipsychotics are basic amines that are mostly charged at physiological pH. As long as a small fraction of the drug (1% is more than enough) is uncharged, the uncharged fraction will pass through a lipid membrane, and the equilibrium is essentially instantaneous so there is always the same fraction that is uncharged.
- If there is sufficient time to reach equilibrium, being mostly charged should not affect the ultimate concentration in the brain.

Question 10

Assuming no active transporters (which is actually not a good assumption), the degree of ionization of penicillin affects:

Answer 10

• The rate of passage through a cell membrane
• The degree of ionization should affect the rate of transfer through a membrane (a difference in the concentration of unionized drug is the driving force for reaching equilibrium) but not the equilibrium concentrations

Question 11

The concentration of penicillin in the CSF is lower than that in the blood. This is because of

Answer 11

• An active pump in the blood brain barrier that pumps it back into the blood
  
  • The fact that some of the penicillin is protein bound, and the protein concentration is higher in the blood than in the CSF
  • As long as there is a small amount of unionized drug it should get through membranes.

Question 12

If you heated cocaine from a plant in a crack pipe, it would:

Answer 12

• Pyrolyze i.e. decompose
  
  • In general the forces between ions are quite strong and so salts are not volatile. Therefore, if you heat salts of organic compounds they pyrolyze.

Question 13

If you converted cocaine into the “free base” by treating it with a stronger base and heated it, it:

Answer 13

Turn into a vapor which you could inhale

Question 14

If you compare the effects of “regular” cocaine (i.e. the salt) with that of the free base after IV injection

Answer 14

There would be no difference
Once the cocaine enters the body it does not matter what form it was originally in, the degree of ionization will be determined by the local pH which is 7.4.

Question 15

Chondroitin sulfate is a polymer of carbohydrate derivatives with an estimated molecular weight of 50 kDa. It is sold for the treatment of osteoarthritis in combination with glucosamine which is a sugar with an amino group on it.

Answer 15

• These agents are unlikely to be effective because oral bioavailability would be low
  
  • Even if the bioavailability of one or both agents is low, there could still be some biological effect

Question 16

A physician calls to say that he has a patient with an intestinal C.diff. The usual treatment for this organism is either vancomycin or metronidazole. It turns out that this patient is breast-feeding her baby, and the physician wants to know if either of these drugs is safe for use in this situation. Both drugs can cause toxicity under certain circumstances.
Vancomycin is an unusual glycopeptide with a molecular weight of about 1,500, and the structure of metronidazole is shown below. Your advice to the physician should be:

Answer 16

Use vancomycin because it will not be absorbed and therefore cannot have effects on the fetus. In contrast, metronidazole can get through the placenta to the fetus, and given that it has a nitro group, it could be toxic

Question 17

There have been many deaths associated with vaping-induced lung damage. Most of the products responsible for the lung damage involved tetrahydrocannabinol (THC) rather than nicotine, and yet we know that smoking marijuana does not cause this type of lung damage. Why would THC vaping products be more dangerous than nicotine vaping products?

Answer 17

• Nicotine is soluble in water but THC is not. Therefore, in general, nicotine vaping products are usually formulated in water. They may be addicting and cause other problems, but they do not cause relatively acute lung damage.
  In contrast, THC vaping products cannot be formulated in water, and some of the lipid-based THC formulations can cause severe lung damage. Lipids such as vitamin E acetate may be innocuous when taken orally, at least at reasonable doses, but they can cause serious lung damage when inhaled