Module 2: Solubility, Absorption.

Should your answer to the paramedic be to go ahead and give the diazepam IM or to not bother and why?

- He should not bother, because the diazepam would precipitate in the muscle and the rate of reabsorption would be very, very slow. - Thus, the serum concentration of diazepam from an IM injection would be well below the therapeutic level. Midazolam is more water soluble than diazepam so it is an acceptable alternative, but with longer onset than an IV benzodiazepine.

Why is it that the formulation of these drugs is mostly propylene glycol and alcohol?

- This is because these drugs have very low water solubility. It is not because the alcohol makes the formulation sterile. Formulations need to be prepared so that they are sterile without alcohol.

According to the structure of cocaine shown below, is cocaine a strong base, weak base or an acid? See image "Cocaine"

- it is a strong base because it is an aliphatic amine, and the nitrogen is not connected to any double bonds.

In the coca plant, cocaine would be mostly ionized or unionized?

- it would be mostly ionized, because it can be assumed that the pH of the plant is close to neutral.

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

- 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 metabolism clearance and instability in the GI tract, which is again an issue for nitroglycerine.

How might proton pump inhibitors affect oral bioavailability?

- this is because many drugs are basic, but require an acidic environment in which they become positively charged that that increases their water solubility. - Of the oral drugs that have been recently approved, more than 50% have significantly decreased oral bioavailability in patients on proton pump inhibitors.

The initial blood concentration of diazepam after IV administration is much greater than with oral diazepam, and therefore the total exposure to the drug is also greater. is this true or false?

- this is false, because the oral bioavailability of diazepam is almost 100% so the total area under the curve (total exposure) is basically the same. It is just the shape of the curve that is different.

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

- this is not correct, because 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. - Thus, if there is sufficient time to reach equilibrium, being mostly charged should not affect the ultimate concentration in the brain.

A physician calls to say that he has a patient with an intestinal Clostridium difficile infection (this organism makes a toxin that can cause pseudomembranous colitis which can be very serious). 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 what? See image "Metronidazole"

- my advice is that the physician should use vancomycin as it would not be absorbed and therefore cannot have effects on the fetus. As opposed to metronidazole which can get through the placenta to the fetus and could be toxic since it has a nitro group. - The C difficile infection is in the intestine so the drug does not need to be absorbed. - the best long term treatment would be a fecal transplant because recurrence rate is much better than when patients are treated with antibiotics.

The fraction of penicillin that is unionized at pH 7.4 is: See image "Pen G Structure"

- since the pH is greater than pKa in this acid, then it is mostly ionized (99.99%), so <0.01% would be unionized. - calculation is 7.4-2.8 = 4.6 -> 10^4.6 = 39811. so only one part in 39811 is unionized which is less than 0.01%. *If the pH is >pKa for an acid or <pKa for a base it will mostly be ionized*

The degree of ionization in the urine (assuming a pH of 5) would be: see image "ASA"

- since the pH of 5 is > than the pKa of 3 in this acid, then it will be mostly ionized. - calculation is 5-3=2 -> 10^2 = 100, so only one part of 100 is unionized, so 99% is ionized.

The degree of ionization of salicylic acid in the blood (lets assume 7 rather than 7.4 to make the calculation easier) is: see image "ASA"

- since the pH of 7 is greater than the pKa of 3 in this acid, then it would be mostly ionized. - calculation is 7-3=4 , -> 10^4= 10000, so only one part of 10000 is unionized. that means it is 99.99% ionized.

If the pH of the urine were increased to 8 by treating a child with bicarbonate, and again assuming equilibrium between the unionized form of salicylate, the ratio of the concentration in the urine to that in the blood would become:

- since the pH of 8 in the urine is greater than the pKa of 3 in this acid, it is mostly ionized. - calculation is 8-3=5 -> 10^5= 100000, so one part in 10000 is unionized. - for blood, calculation is 7-3=4 , -> 10^4= 10000, so only one part of 10000 is unionized. - thus the ratio of concentration in urine to blood becomes , 100000:10000 = 10:1 *so here the concentration in the urine is higher than in the blood and this increases the rate of urinary clearance. this is an example of ion trapping*

Assuming no active transporters (which is actually not a good assumption), what does the degree of ionization of penicillin affect?

- the degree of ionization would affect the rate of passage through a cell membrane, since a difference in the concentration of unionized drug is the driving force for reaching equilibrium, but it would not affect the equilibrium concentrations.

When the child arrives he is given IV diazepam but should you be mindful of anything?

- the diazepam may precipitate in the blood, but it will form small crystals in the rapidly moving blood stream and redissolve rapidly causing no problems.

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

- the major determinant of tmax for most drugs is gastric emptying. - 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

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. Are these agents effective for the treatment of osteoarthritis, why or why not?

- the most recent and best study of this combination showed no therapeutic benefit for the treatment of osteoarthritis. - the agents are unlikely to be effective because oral bioavailability would be low.

What are some characteristics that would prevent a drug from being well absorbed from the intestine?

- Being 100% ionized at pH7 (I.e. quaternary amine) - having many functional groups that are ionized or can hydrogen bond to water.

There have been many deaths associated with vaping-induced lung damage. Most of the products responsible for 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?

- This is because nicotine is soluble in water but THC is not. Therefore, in general, nicotine vaping products are usually formulated in water, and although they may be addicting and cause other problems, they do not cause relatively acute lung damage. - However, THC vaping products cannot be formulated in water, and some of the lipid-based THC formulations can cause severe lung damage. One of the commonly used lipids is Vitamin E acetate which can cause serious lung damage when inhaled.

Why are paramedics and most other health care professionals not permitted to give drugs intravenously?

- This is because 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 blood concentration levels are produced and there little time for redistribution of the drug to tissues such as fat.

The concentration of penicillin in the CSF is lower than that in the blood. why is this?

- This is because there is an active pump in the blood brain barrier that pumps it back into the blood - also some of the penicillin is protein bound, and the protein concentration is higher in the blood than in the CSF

Aspirin poisoning is a significant issue in children. It is rapidly hydrolyzed to salicylic acid, and therefore most of the toxicity is actually due to the salicylic acid. It is important to increase the clearance of salicylic acid in a case of poisoning. The major clearance of salicylic acid is renal. The following questions should provide a clue as to how the renal clearance of salicylate can be increased. The structure of salicylic acid is given below. From its structure and pKa, is salicylic acid a strong acid, strong base, weak acid or neutral? see image "ASA"

- a strong acid because it's pKa of 3 suggests that it would be a strong acid or weak base, and since it is a carboxylic acid, it is a strong acid.

How does drug solubility affect oral bioavailability?

- for a drug to be absorbed it must be in solution. The solubility does not need to be high because of the long transit time in the intestine, but it needs to have a reasonable degree of water solubility.

Assuming the ratio of unionized salicylic acid in the blood and urine are in equilibrium, what would be the approximate ratio of the total concentration in the urine to that in the blood?

- if you set up a table in which the concentration of unionized drug is arbitrarily set to 1, assuming no transporters, the unionized drug will have the same concentration in the blood and urine because it is the form that freely diffuses across membranes. - if the concentration of the unionized drug is 1, the concentration of ionized drug in the urine at pH5 must be 100, and in the blood at pH7 must be 10000. - Thus, the unionized concentration is not significant in either blood or urine relative to the ionized concentration, since they are both 1, so the total concentration in the urine and blood is essentially the same as the ionized concentration - > 100:10000 = 1:100 *as you can see, the concentration in the blood is higher in the blood than in the urine, so urinating (aka renal excretion) is not a very efficient way to eliminate salicylate. *

The textbook also says that penicillins are not very lipid-soluble and, therefore, penetrate poorly from blood into the brain; however, a high concentration of penicillin can be obtained by intrathecal injections into the CSF (cerebrospinal fluid). From the structure and pKa, is penicillin G a strong acid, weak base, strong base or neutral? See image "Pen G Structure"

- it is a strong acid, because the pKa of 2.8 indicates that it will be either a strong acid or weak base. And since it has a carboxylic acid group, we know it is a strong acid.

Given the pKa and structure of phenytoin, it is: a strong base or weak acid and how much is ionized? See Image "diazepam and phenytoin"

- it is a weak acid because both nitrogens are part of amide groups so it is not basic. and only about 10% ionized, because since physiological pH is 7.4 which is <pKa this is acid is not mostly ionized. *If the pH is >pKa for an acid or <pKa for a base it will mostly be ionized*

Given the structure of diazepam: is it a weak or strong base or acid, and what part of it is protonated or ionized? See Image "diazepam and phenytoin"

- it is a weak base, because there is no carboxylic acid or other group that could be a strong acid. And it has two nitrogens, one is an amide so it is not basic. While the other is an imine, and the double bond decreases the electron density on the nitrogen and makes it a weaker base than a simple amine. - Thus the imine would be partially protonated. - If the pH is >pKa for an acid or <pKa for a base it will be mostly ionized. This is not the case since the physiological pH is 7.4 which is >pKa and thus this base is not mostly ionized. *If the pH is >pKa for an acid or <pKa for a base it will mostly be ionized*

If you heated cocaine from a plant in a crack pipe, would it turn into a vapour you could inhale or pyrolyze (i.e. decompose)?

- it would pyrolyze because it is mostly ionized, and in general the forces between ions are quite strong and so salts are not volatile (easily evaporated at normal temperatures) .

If you converted cocaine into the "free base" by treating it with a stronger base and heated it, would it turn into a vapour you could inhale or would it pyrolyze?

- it would turn into a vapour you could inhale, because after you treat it with a stronger base, cocaine is not a salt anymore and it will have a significant vapour pressure. - so if you heat it to increase its vapour pressure it is sufficient to get a pharmacological dose through inhaling the vapours.

Please use the following scenario to answer questions 1-9. Clinical Scenario: An eight year old child is in status epilepticus and is being brought in by an ambulance. The paramedic calls from the ambulance and asks if he can give the child an IM injection of diazepam to stop the seizures. Background: Status epilepticus is a continuous seizure. This is a life-threatening medical emergency. It is usually treated with IV diazepam or lorazepam. Diazepam (Valium) is a benzodiazepine that is useful for the acute treatment of seizures, but tolerance to the anticonvulsant properties usually develops over a period of days or weeks, and so it is not usually used for chronic therapy, and after the acute response a different anticonvulsant is started such as phenytoin. The half-life of diazepam is about 43 hours. Phenytoin is one of the most common anticonvulsants. The parenteral formulation of these drugs is in propylene glycol/water. The structure of these drugs are shown below. See Image "diazepam and phenytoin" The pKa of diazepam is 3.4. If you did not know the structure of diazepam, what does the pKa of 3.4 indicate?

- the pKa of 3.4 would indicate that it could be a strong acid or a weak base.

If you compare the effects of "regular" cocaine (i.e. the salt) with that of the free base after IV injection, would there be a difference?

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

The seizures stop with the IV diazepam, what should you do next?

- you should give phenytoin within the first hour to prevent recurrence of seizures. - This is because diazepam is lipid soluble and redistributes to fat. So after about an hour, this redistribution will lead to sub-therapeutic levels of diazepam, thus you will need to administer phenytoin or some other anticonvulsant after to prevent recurrence of seizures.

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.

1) instability in stomach acid - penicillin has some instability in stomach acid so you have to give higher dose 2) degraded by pancreatic enzymes - proteins such as insulin 3) Insolubility - ketoconazole in patients on PPIs 4) metabolized by gut bacteria - digoxin in 10% of patients with a specific bacteria that metabolizes digoxin. 5) poor absorption because of permanent charge or high degree of hydrogen bonding to water - quaternary amines such as neostigmine 6) high first pass metabolism - nitroglycerine 7) substrate for transporter that pumps the drug back into the gut lumen - digoxin but oral bioavailability still sufficient. 8) need for rapid response - epinephrine for anaphylaxis 9) need to make sure of therapeutic drug level because of potentially fatal disease - antibiotics for subacute bacterial endocarditis