Part I. Structures, Reactions, Etc. — Fill in All Boxes

1. Name the enzyme responsible for catalyzing the first reaction (Ad = adenosine) and draw the structure of the product of the second reaction.

2. Draw the predominant form of the following drug when placed in a pH 7.4 environment.

3. Draw the structures of the products of each of the following reactions (you may use partial structures when only one part of a molecule is affected).

4. Draw the structure of an alpha-sympathomimetic that is biotransformed to the following metabolite.

5. Draw structures for each of the products of the following reactions (OOD = oxidative O-dealkylation).

6. Draw structures of the two metabolites generated by the following biotransformation pathways.

7. Draw the structure of the product of the following reaction.

Correct answers shown in RED.

8. Which of the following statements most accurately describes drug 1 and 2.

(1) Both drugs are direct-acting sympathomimetics. The R-isomer of drug #1 is the active form while the S-isomer of drug #2 is active. Both drugs are substrates for MAO.

(2) Drug #1 is a direct-acting sympathomimetic while drug #2 is an indirect-acting sympathomimetic. Both drugs would be substrates for COMT but only drug #1 would be inactivated by MAO.

(3) Drug #2 is more lipophilic than drug #1 and therefore more likely to enter the CNS. Both drugs will exhibit sympathomimetic activity with drug #2 having a greater indirect-mode of action than drug #1.

(4) Drug #1 is an adrenergic alpha1-agonist while drug #2 stimulates the release of stored NE. Drug #2 requires bioactivation by dopamine ß-hydroxylase in order to produces nonselective alpha-agonism.

9. Which of the following statements most accurately describes -methyldopa and metyrosine.

(1)Both drugs act in the CNS promoting release of NE from presynaptic neurons by interacting with adrenergic receptors. alpha-Methyldopa is a prodrug but metyrosine is not.

(2) Both drugs are prodrugs but alpha-methyldopa acts centrally while metyrosine inhibits dopamine beta-hydroxylase in the PNS.

(3) Both drugs inhibit the enzyme tyrosine hydroxylase. Alpha-Methyldopa has a slow onset of action primarily because it must be bioactivated in the nerve ending.

(4) Alpha-Methyldopa is converted to an alpha₂-agonist that acts in the CNS to decrease sympathetic tone and reduce blood pressure. Metyrosine, a tyrosine hydroxylase inhibitor, inhibits the biosynthesis of catecholamines in peripheral systems.

10. Which of the following descriptions most accurately describes the storage and release of NE in adrenergic neurons.

(1) NE is stored in granules to spare it from MAO catabolism and provide a concentrated form for release. NE release is associated with an influx of Ca²⁺ into the nerve ending.

(2) The release of NE is regulated by presynaptic alpha1-adrenoceptors. Alpha1-Adrenoceptor agonists inhibit NE release.

(3) NE is formed in the storage granules from DA catalyzed by tyrosine hydroxylase. Stored NE is complexed with molecules such as ATP.

(4) NE is stored in granules to protect from MAO and provide a concentrated form for release. The release of NE is initiated by an action potential that causes Ca²⁺ to flow out of the neuron.

11. Which of the following descriptions most accurately describes guanfacine and guanadrel.

(1) Both drugs are adrenergic neuronal blocking agents producing their therapeutic antihypertensive effects by depleting prejunctional NE levels.

(2) Guanfacine is more basic than guanadrel and is therefore more highly cationized at physiologic pH. Guanfacine is translocated by neuronal Uptake1 and displaces stored NE.

(3) Both drugs are guanidine derivatives that interact with adrenergic neurotransmission in the PNS. The bulky, lipophilic ring system of guanadrel facilitates the binding of this drug to the alpha2-adrenoceptor.

(4) Both drugs are guanidine derivatives with guanadrel > guanfacine in basicity. The bulky aromatic structural feature of guanfacine facilitates the "fit" of this structure to the NE alpha2-adrenoceptor.

12. Which of the following descriptions most accurately describes the following three drugs.

(1) Bretylium is a quaternary ammonium salt that is used parenterally as a sympatholytic antiarrhythmic agent. Methoxamine is a selective alpha1-sympathomimetic and dipivefrin is a prodrug of epinephrine.

(2) Methoxamine is a alpha2-sympathomimetic and dipivefrin is a catecholamine prodrug administered ophthalmically. Bretylium is an adrenergic neuronal blocker guanidine derivative.

(3) All three drugs are therapeutically useful for their sympathomimetic actions. Methoxamine and dipivefrin are direct-acting sympathomimetics while bretylium is an indirect-acting agonist.

(4) Dipivefrin is a short-acting beta-blocker that, like bretylium, is used as a parenteral antiarrhythmic agent. Methoxamine is a prodrug that is converted metabolically to the hyptensive agent midodrine.

13. Which of the following descriptions most accurately describes transduction processes associated with adrenergic neuronal function.

(1) All alpha-receptors are coupled to a G-protein that activates phospholipase C. alpha2 and beta-receptors are coupled to G proteins that activate adenylyl cyclase.

(2) Agonist action at alpha1-receptors results in both Ca²⁺-channel and phospholipase C activation. The amplifier for beta-adrenoceptors is adenylyl cyclase.

(3) Agonist action at all adrenoceptor subtypes is mediated by the second messenger ATP which is formed in cells by the action of phosphodiesterase.

(4) Beta1 and beta2-adrenoceptors are linked to an inhibitory G protein while alpha2-receptors are linked to a stimulatory G protein. Both G-proteins alter intracellular cAMP concentrations.

14. Which of the following descriptions most accurately describes propranolol and atenolol.

(1) Atenolol is a beta2-selective antagonist while propranolol is a nonselective -blocker. Both drugs are marketed as racemic mixtures. The basic secondary amine moiety in both drugs is required for receptor affinity.

(2) Atenolol is a beta1-selective antagonist while propranolol is a nonselective, ß1 and ß2-blocker. Both drugs are marketed as mixtures of the S and R enantiomers. Comparison of structures indicates that propranolol is more lipid soluble.

(3) Propranolol is more lipophilic than atenolol and therefore exhibits pharmacological actions resulting from action in the CNS. Aromatic hydroxylation is the primary metabolic transformation of atenolol.

(4) Atenolol is converted to an active metabolite that has a longer half-life than the parent drug. Propranolol is not extensively metabolized and is eliminated primarily as the parent drug.

15. Which of the following descriptions most accurately describes pindolol and metoprolol..

(1) Both drugs are ß-adrenoceptor antagonists useful in the management of hypertension. Metoprolol is a cardioselective ß-blocker having greater affinity for ß2-adrenoceptors than the ß1-subtype.

(2) Both drugs are ß-adrenoceptor antagonists useful in the management of hypertension. Pindolol is a cardioselective ß-blocker having greater affinity for ß1-adrenoceptors than the ß2-subtype.

(3) Pindolol can be metabolized by aromatic hydroxylation. Metoprolol is a cardioselective ß-blocker having greater affinity for ß1-adrenoceptors than the ß2-subtype.

(4) Metoprolol, a selective ß1-adrenoceptor antagonist, can be metabolized by CYP450-enzyme catalyzed aromatic hydroxylation.

16. Which of the following descriptions most accurately describes labetalol and carvedilol.

(1) Both drugs exist as a two optical isomers and each isomer is equipotent in regard to adrenolytic action. The ß to alpha adrenolytic potency ratio of labetalol is much higher than for carvedilol.

(2) Both structures can be dissected to contain a component responsible for ß-blockade and a component for alpha-adrenolysis. Dual alpha/ß-blockade may offer more efficacious antihypertensive efficacy.

(3) Both drugs have one chiral center giving rise to 4 optical isomers which tends to complicate their pharmacological and therapeutic profiles as dual alpha/ß-blocker.

(4) Carvedilol has a ß to alpha blocking potency ratio that is near 1.0 and its use is often associated with a high incidence of postural hypotension.

17. Which of the following descriptions most accurately describes prazosin and terazosin..

(1) Both drugs have high antagonistic activity at postjunctional alpha1-adrenoceptors and therefore reduce peripheral resistance making them useful antihypertensives. Terazosin has a longer duration of action than prazosin.

(2) Prazosin has greater affinity for prostatic alpha1-adrenoceptors than terazosin and its agonist activity at these receptors is therapeutic for benign prostatic hyperplasia.

(3) Both drugs have comparable elimination half-lives as a result of extensive metabolism by O-demethylation. Terazosin has higher oral bioavailability because of greater lipid solubility.

(4) Both drugs are efficacious alpha-blockers at central CNS presynaptic sites. Both drugs are used in the management of hypertension. Terazosin is the reduced-furan analogue of prazosin.

18. Which of the following most accurately describes drugs A and B.

(1) Both drugs are direct-acting 2-sympathomimetics useful in treating hypotensive conditions. Drug A is a substrate for COMT while drug B will be metabolized in the GIT by sulfatase enzymes.

(2) Drug A is a ß-arylethanolamine derivative having beta-adrenoceptor blocking activity. It is a good substrate for MAO. Drug B is a catecholamine derivative having -sympathomimetic activity.

(3) Drug A, a catecholamine derivative and drug B, a resorcinol derivative are useful bronchodilators administered by an oral route for systemic action.

(4) Drug A, a catecholamine derivative and drug B, a saligenin derivative are both beta-adrenoceptor agonists having bronchodilatory actions. Drug B is more metabolically stable than drug A because it is not a substrate for COMT.

19. Select one of the following that most accurately describes possible metabolic transformations of propranolol.

(1) Oxidative O-dealkylation, alcohol glucuronidation, esterase hydrolysis

(2) Alcohol glucuronidation, oxidative N-dealkylation, oxidation to a carboxylic acid metabolite

(3) MAO deamination, COMT methylation, oxidative N-dealkylation to an aldehyde metabolite

(4) Aromatic hydroxylation, oxidative N-dealkylation, amidase hydrolysis, alcohol glucuronidation.

20. Select one of the following that most accurately characterizes the drug structure designed as a 2-sympathomimetic bronchodilator.

(1) This structure is a highly potent bronchodilator having excellent oral bioavailability.

(2) This structure is a highly potent bronchodilator with relatively low oral bioavailability because it contains a catechol structural feature.

(3) This structure has a short elimination half-life because it is easily metabolized. While it is a potent beta2-sympathomimetic bronchodilator it is unsuitable for maintenance therapy.

(4) This structure lacks adrenoceptor selectivity and would not be suitable for systemic therapy due to high metabolic lability.

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