Patient Case: Mr. Jones, a 52 year old bus driver, is brought to the emergency d
ID: 952749 • Letter: P
Question
Patient Case:
Mr. Jones, a 52 year old bus driver, is brought to the emergency department by paramedics. He has been experiencing dizziness, throbbing headaches, and weakness for two days. This morning, he had a nose bleed. His wife called 911 after measuring his BP which was 185/120. He is 5' 10” and weighs 287 lbs. The ER physician starts him on an IV -blocker. Since the ER physician didn’t have further information, he chose propranolol, a non-selective -blocker. Soon after starting the infusion, Mr. Jones shows signs of having difficulty breathing and his blood oxygen level starts to drop. When the physician contacts the patient’s wife to inquire about other medication that Mr. Jones usually takes, he learns that Mr. Jones is suffering from asthma and uses an inhaler with terbutaline (2-selective sympathomimetic) to control the symptoms. The ER physician stopped the IV propranolol and started Mr. Jones on metaprolol, a selective -blocker. After his blood pressure is finally stabilized in the ER, he is started on hydrochlorothiazide, a thiazide diuretic, as a first step in his out-patient treatment.
-adrenergic Antagonists:
Scottish scientist James W. Black developed propranolol in the 1960s. In 1988, he was awarded the Nobel Prize in Medicine for this discovery. Propranolol was derived from the early -adrenergic antagonists dichloroisoprenaline and pronethalol. The key structural modification, which was carried through to essentially all subsequent beta blockers, was the insertion of a methoxy bridge into the arylethanolamine structure of pronethalol thus greatly increasing the potency of the compound. This modification also apparently eliminated the carcinogenicity found with pronethalol in animal models. Newer, more selective beta-blockers (such as nebivolol, carvedilol, or metoprolol) are now used in the treatment of hypertension. Propranolol is a available as IV and PO. When administered orally, it is rapidly and completely absorbed, with peak plasma levels achieved approximately 1–3 hours after ingestion. Co-administration with food appears to enhance bioavailability. Despite complete absorption, propranolol has a variable bioavailability due to extensive first-pass metabolism. Hepatic impairment will therefore increase its bioavailability. The main metabolite 4-hydroxypropranolol, with a longer half-life (5.2–7.5 hours) than the parent compound (3–4 hours), is also pharmacologically active. Propranolol is a highly lipophilic drug that achieves high concentrations in the brain. The duration of action of a single oral dose is longer than the half-life and may be up to 12 hours, if the single dose is high enough (e.g., 80 mg). Effective plasma concentrations are between 10–100 ng/mL. Noradrenaline and adrenaline are the natural messengers for the 1 receptors of the heart. Analogs of these natural messengers have been developed through medicinal chemistry techniques. Isoprenaline is an agonist, whereas pronethalol is a partial agonist and, as discussed, propanolol is an antagonist.
Unfortunately, propranolol acts against both 1 and 2 receptors. This is particularly problematic for asthmatic patients because antagonism of the 2 adrenoreceptors is known to constrict airways. The active sites of the 1 and 2 receptors are depicted below, with a lead compound bound in the respective active sites. In the 1 receptor site, X can be either an oxygen or nitrogen depending on the person’s ethnicity.
Metoprolol oral absorption is rapid and complete. Plasma levels following oral administration, however, reach only 50% of levels following intravenous administration, indicating about 50% first-pass metabolism. Plasma levels achieved are highly variable after oral administration of metoprolol. Only a small fraction of the drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of R- and S-enantiomers. Metoprolol is extensively metabolized by the cytochrome P450 enzyme system in the liver. The oxidative metabolism of metoprolol is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6), with marked ethnic differences in the prevalence of the poor metabolizers. Approximately 7% of Caucasians and less than 1% Asian are poor metabolizers. Poor CYP2D6 metabolizers exhibit several-fold higher plasma concentrations of metoprolol than extensive metabolizers with normal CYP2D6 activity. The elimination half-life of metoprolol is about 7.5 hours in poor metabolizers and 2.8 hours in extensive metabolizers. However, the CYP2D6 dependent metabolism of metoprolol seems to have little or no effect on safety or tolerability of the drug. None of the metabolites of metoprolol contribute significantly to its beta-blocking effect. TOPROL-XL (metoprolol succinate) has been formulated to provide a controlled and predictable release of metoprolol for once-daily administration. The tablets comprise a multiple unit system containing metoprolol succinate in a multitude of controlled release pellets. Each pellet acts as a separate drug delivery unit and is designed to deliver metoprolol continuously over the dosage interval.
Additional Facts:
A. The Kd of propranolol for the receptor is 10 nM.
Assume a simple equilibrium. Let R=receptor and P=propranolol
where
R + P RP Keq=[RP]/[R][P]=Kd
B. 50% propranolol given orally is absorbed into the blood stream.
C. Blood volume is 5 L.
D. The molecular weight of propranolol is 259.35 g/mol
E. The in vivo half-life of propranolol is 10 hours.
Questions:
1. Based on the natural messengers, agonists, partial agonists, and antagonist structures presented in the case, which of the following conclusions is valid?
a) Phenol groups are not required to reduce receptor activity.
b) The natural messengers benefit from additional Van der Waals interactions not present in the antagonist and partial agonist compounds.
c) Switching the position of the substituent off of the conserved aromatic ring will enhance the activity of the receptor.
d) A and C
e) None of the above.
2. What medicinal chemistry strategy would be best in designing second-generation beta-blockers thatmay exhibit a higher degree of specificity for the 1 receptor?
a) Adding a hydrophobic group off of the aromatic ring will provide additional van der Waals interactions with the 1 receptor.
b) Adding a hydrogen-bonding group off of the bridging oxygen will provide additional hydrogen bonding interactions with the 1 receptor.
c) Adding a second aromatic group, in the form of a naphthalene ring, will provide additional selectivity for the 1 receptor based on increased hydrogen bonding interactions.
d) Adding a hydrogen-bonding group off of the aromatic ring may provide additional hydrogen bonding interactions with the 1 receptor.
e) None of the above strategies would be an advisable strategy for developing second-generation beta-blockers with enhanced selectivity for the 1 receptor.
3. Why is the IV propranolol infusion causing Mr. Jones problems to breathe?
a) Propranolol is a partial agonist at alpha-adrenergic receptors that are present on smooth muscles in the lungs and cause contraction?
b) Bronchial smooth muscles contain 2-adrenergic receptors that cause relaxation when activated and propranolol blocks activity of the endogenous agonists noradrenaline and adrenaline.
c) Propranolol should be given orally to avoid such complications, because the drug will desensitize adrenergic receptors when given too fast.
d) Propranolol reduces the net output of the heart and therefore less blood is pumped through the lungs, leading to lower oxygen supply.
e) The combination of terbutaline and propranolol is known to cause this side effect even in healthy individuals.
4. The thiazide diuretic that Mr. Jones was started on, which works at the distal convoluted tubule, may:
a) Cause a decrease in blood pressure
b) Deplete potassium
c) Increase blood sugar levels
d) Increase blood uric acid levels
e) All of the above
5. The thiazide diuretic did not provide satisfactory control of Mr. Jones’ blood pressure. At his follow-up outpatient visit, another medication was added and his pressures are now controlled. This experience has frightened him and he is resolved to loose weight, stop smoking, and exercise. He is very consistent in taking his medication. Three months and thirty pounds lighter, Mr. Jones begins to experience a dry, non-productive cough unrelieved by over the counter medication. Mr. Jones goes to his family doctor who thinks the cough is from one of the two medications he takes. The most likely drug cause of the cough is:
a) Hydrochlorothiazide (thiazide diuretic)
b) Amlodipine (calcium channel blocker)
c) Nadolol (beta blocker)
d) Lisinopril (angiotensin-converting enzyme (ACE) inhibitor)
6. Which of the following will impact the bioavailability of propranolol?
a) Food intake
b) Hepatic function
c) Route of administration
d) All of the above
e) None of the above
7. Using Additional Facts in the Case: If you want to have 80% of the receptor saturated, assuming a simple equilibrium with one propranolol molecule binding to one protein receptor. What molarity of propranolol do we require?
a) 5 x 10^-7 M
b) 1 x 10^-8 M
c) 4 x 10^-7 M
d) 5 x 10^-8 M
e) 4 x 10^-8 M
8. Using Additional Facts in the Case: About how many mg of propranolol should you give the patient?
a) 2000 mg
b) 520 mg
c) 250 mg
d) 0.104 mg
e) 520 mg
9. Using Additional Facts in the Case: You want the amount of receptor-propranolol to never drop below 25% of the initial concentration. How often do you need to administer the propranolol to the patient?
a) 2.5 hrs
b) 20 hrs
c) 25 hrs
d) 30 hrs
e) 40 hrs
10. Poor CYP2D6 metabolizers who are on metoprolol may experience:
a) More metoprolol induced adverse effects
b) Less metoprolol induced adverse effects
c) No change in metoprolol induced adverse effects
d) None of the above
e) All of the above
11. The controlled release formulation of metoprolol (Toprol-XL) provides better patient compliance because:
a) It is dosed once per day
b) It is dosed twice per day
c) It has less adverse effects compared to metoprolol immediate release formulations.
d) None of the above
e) All of the above
Explanation / Answer
Solution:
1) Both A and C
2) Option C
3) Option B
4) Option A
5) Option D
6) Option C
7) Option C
8) Option C
9) Option A
10) Option B
11) Option A