Pharmacokinetics

Question 1

The rates of oral absorption of sedative-hypnotics differ
depending on a number of factors, including lipophilicity. For
example, the absorption of ________ is extremely rapid, and
that of __________ and the_____________** **is
more rapid than other commonly used benzodiazepines.

Answer 1

triazolam

diazepam

active metabolite of clorazepate

Question 2

_____________-, a prodrug, is converted to its active form,

• *desmethyldiazepam (nordiazepam),** by acid hydrolysis in the
• *stomach.**

Answer 2

Clorazepate

Question 3

Most of the barbiturates and other older sedativehypnotics,
as well as the newer hypnotics _______,________ and __________, are absorbed rapidly into the blood following oral
administration.

Answer 3

(eszopiclone, zaleplon,
zolpidem

Question 4

Most of the barbiturates and other older sedativehypnotics,
as well as the newer hypnotics (eszopiclone, zaleplon,
zolpidem), are absorbed rapidly into the blood following oral
administration.

Question 5

• *Metabolic transformation to more water-soluble metabolites** is
• *necessary** for clearance of sedative-hypnotics from the body.

The** microsomal drug-metabolizing enzyme systems** of the liver are** most important i**n this regard, so elimination half-life of these drugs
depends mainly on the rate of their metabolic transformation.

Question 6

Melatonin receptors are thought to be involved in maintaining
circadian rhythms underlying the sleep-wake cycle (see
Chapter 16 ).

___________, a novel hypnotic drug
specifically useful for patients who have difficulty in falling
asleep, is an agonist at MT 1 and MT 2 melatonin receptors
located in the suprachiasmatic nuclei of the brain.

The drug has no direct effects on GABAergic neurotransmission in the
central nervous system

Answer 6

Ramelteon (Rozerem)

Note:

. In polysomnography studies of patients with chronic insomnia, ramelteon reduced the latency of persistent sleep with no effects on sleep architecture and no rebound insomnia or significant withdrawal symptoms.

Ramelteon has minimal potential for abuse, is not
a controlled substance,andregular use does not result in
dependence. The drug is rapidly absorbed after oral administration andundergoes extensive first-pass metabolism,forming anactive metabolite with longer half-life (2–5 hours) than the parent drug.

Question 7

The___________isoform of cytochrome P450 is mainly responsible for the metabolism of ramelteon, but the CYP2C9 isoform is also involved.

The drug should not be used in combination with inhibitors of CYP1A2 (eg, ciprofloxacin, fluvoxamine, tacrine, zileuton) or CYP2C9 (eg, fluconazole) and should be used with **caution in patients with liver dysfunction. **

Answer 7

CYP1A2

Question 8

The CYP inducer_________markedly reduces the
plasma levels of both ramelteon and its active metabolite.

Answer 8

rifampin

Question 9

Adverse effects of ramelteon include ______________. Ramelteon is an FDA pregnancy
category C drug.

Answer 9

• dizziness,
• somnolence,
• fatigue, and
• endocrine changes as well as
• decreases in testosterone
• and increases in prolactin

Question 10

. Ramelteon is an FDA pregnancy
category__________drug.

Answer 10

C

Question 11

_____________ has selective anxiolytic effects, and its pharmacologic
characteristics differ from those of other drugs described
in this chapter.

Answer 11

Buspirone

Question 12

Buspirone relieves anxiety without causing
_________________

Answer 12

marked sedative, hypnotic, or euphoric effects.

Question 13

What is the difference of buspirone with benzodiazepines?

Answer 13

Unlike benzodiazepines,
the drug has no anticonvulsant or muscle relaxant
properties.

Buspirone does not interact directly with
GABAergic systems.

It may exert its anxiolytic effects by acting
as a partial agonist at brain 5-HT 1A receptors, but it also
has affinity for brain dopamine D 2 receptors.

Question 14

Where does **buspirone **may exert its anxiolytic effects ?

Answer 14

by acting
as a** partial agonist at brain 5-HT 1A receptors,** but it also
has affinity for brain dopamine D 2 receptors.

Question 15

Buspironetreated
patients show no____________

Answer 15

• ** rebound anxiety or withdrawal signs on abrupt discontinuance.**

Question 16

Buspirone is not effective in
blocking the _________ resulting from
abrupt cessation of use of benzodiazepines or other sedativehypnotics.

Answer 16

acute withdrawal syndrome

So wag syang gawing rebound okay kasi d sya effective as rebound

Question 17

Buspirone has minimal abuse liability.

In marked
contrast to the benzodiazepines, the anxiolytic effects of buspirone may take ____________ to become established,
making the drug unsuitable for management of acute anxiety
states.

Answer 17

more than a week

Question 18

Buspirone is indicated for?

Answer 18

The drug is used in generalized anxiety states but is
less effective in panic disorders.

Question 19

Buspirone is** rapidly absorbed orally** but undergoes extensive
first-pass metabolism via** hydroxylation and dealkylation**
reactions to form several active metabolites.

The major metabolite is 1-(2-pyrimidyl)-piperazine (1-PP), which has_____ and which ____________-
It is not known what role (if any) 1-PP plays in the central
actions of buspirone.

Answer 19

• α 2 -adrenoceptor–blocking actions
• enters the central nervous system to reach higher levels than the parent
  drug.

Question 20

The elimination half-life of buspirone is
____________, and liver dysfunction may slow its clearance.

Answer 20

2–4 hours

Question 21

____________, an inducer of cytochrome P450, decreases the halflife
of buspirone;

• *inhibitors of CYP3A4** (eg, erythromycin,
• *ketoconazole, grapefruit juice, nefazodone)** can markedly
• *increase its plasma levels.**

Answer 21

Rifampin

Question 22

What are the advantages of Buspirone _______________

Answer 22

• causes less psychomotor impairment than benzodiazepines and
• does not affect driving skills.
• the drug does **not potentiate effects of conventional sedative-hypnotic **drugs, ethanol, or tricyclic antidepressants, and
• elderly patients do not appear to be more sensitive to its actions.

Question 23

Nonspecific effects of Buspirone?

Answer 23

• chest pain,
• tachycardia,
• palpitations,
• dizziness,
• nervousness,
• tinnitus,
• gastrointestinal distress,
• and paresthesias
• and a dosedependent
• pupillary constriction may occur.
• Blood pressure may be significantly elevated in patients receiving MAO inhibitors.

Question 24

Buspirone is an FDA pregnancy category ____ drug.

Answer 24

B

Question 25

\_\_\_\_\_\_ metabolism accounts for the clearance of all benzodiazepines. The patterns and rates of metabolism depend on the individual drugs.

Answer 25

Hepatic

Question 26

Most benzodiazepines undergo **microsomal oxidation (phase I reactions),** including N- dealkylation and aliphatic hydroxylation catalyzed by cytochrome P450 isozymes, especially CYP3A4. The metabolites are subsequently conjugated (phase II reactions) to form glucuronides that are excreted in the urine. However, **many phase I metabolites of benzodiazepines**are**pharmacologically active**, some with long half-lives ( Figure 22–5 ) . For example,\_\_\_\_\_\_\_\_\_\_\_\_\_, which has an elimination half-life of more than 40 hours, is an active metabolite of **chlordiazepoxide, diazepam, prazepam,** and **clorazepate**.

Answer 26

desmethyldiazepam

Question 27

\_\_\_\_\_\_\_\_\_\_\_\_\_undergo α-hydroxylation, and the resulting metabolites appear to **exert short-lived** pharmacologic effects because they are **rapidly conjugated to form inactive glucuronides**

Answer 27

** Al**prazolam and **tri**azolam " Ill Try ( AL TRI)

Question 28

. The **short elimination** half-life of **triazolam (2–3 hours)** favors its use as a _________ rather than as a sedative drug.

Answer 28

hypnotic

Question 29

The formation of active metabolites has complicated studies on the pharmacokinetics of the **benzodiazepines i**n humans because the elimination half-life of the **parent drug** may have little relation to the time course of pharmacologic effects. Benzodiazepines for which the **parent drug or active metabolites** have **long half-livesare** predictably **more likely to cause** \_\_\_\_\_\_\_\_\_\_\_\_

Answer 29

cumulative effects with multiple doses.

Question 30

In benzodiazepines Cumulative and residual effects such as **excessive drowsiness**appear to be**less of a problem with such drugs** as \_\_\_\_\_\_\_\_\_\_\_\_, which have relatively short half-lives and are metabolized directly to inactive glucuronides. Some pharmacokinetic properties of selected benzodiazepines are listed in Table 22–1 .

Answer 30

estazolam, oxazepam, and lorazepam

Question 31

The metabolism of several commonly used benzodiazepines including **diazepam, midazolam, and triazolam** is affected by inhibitors and inducers of hepatic P450 isozymes (see Chapter 4 ).

Question 32

With the exception of \_\_\_\_\_\_\_\_\_\_\_\_, only **insignificant quantities of the barbiturates** are excreted **unchanged.**

Answer 32

phenobarbital

Question 33

The major metabolic pathways of Barbiturates involve ________ by hepatic enzymes to form **alcohols, acids, and ketones**, which appear in the **urine as glucuronide conjugates**.

Answer 33

oxidation

Question 34

In barbiturates the **overall rate of hepatic** **metabolism** in humans depends on the **individual drug** but (with the exception of the\_\_\_\_\_\_\_\_\_\_) is usually slow.

Answer 34

thiobarbiturates

Question 35

The elimination half-lives of _________ range from **18 to 48 hours** in different individuals.

Answer 35

secobarbital and pentobarbital

Question 36

The elimination half-life of phenobarbital in humans is _________ Multiple dosing with these agents can lead to cumulative effects.

Answer 36

4–5 days.

Question 37

Newer hypnotics— After oral administration of the standard formulation,\_\_\_\_\_\_\_\_ reaches peak plasma levels in **1.6 hours**. A biphasic release formulation extends plasma levels by approximately 2 hours.

Answer 37

zolpidem

Question 38

\_\_\_\_\_\_\_\_\_\_ is rapidly metabolized to inactive metabolites via oxidation and hydroxylation by hepatic cytochromes P450 including the CYP3A4 isozyme. The elimination half-life of the drug is 1.5– 3.5 hours, with clearance decreased in elderly patients.

Answer 38

Zolpidem

Question 39

\_\_\_\_\_\_\_ is metabolized to inactive metabolites, mainly by hepatic **aldehyde** oxidase and partly by the cytochrome P450 isoform CYP3A4. The half-life of the drug is about 1 hour. Dosage should be reduced in patients with hepatic impairment and in the elderly.

Answer 39

Zaleplon

Question 40

\_\_\_\_\_\_\_\_\_\_ which **inhibits both aldehyde dehydrogenase** and **CYP3A4,** markedly **increases the peak plasma level of zaleplon**.

Answer 40

Cimetidine,

Question 41

Barbiturates \_\_\_\_\_\_\_\_ is metabolized by **hepatic cytochromes P450** (especially CYP3A4) to form the inactive N -oxide derivative and weakly active desmethyleszopiclone.

Answer 41

Eszopiclone Note: The **elimination half-life of eszopiclone** is approximately **6 hours** and is **prolonged in the elderly** and in the presence of inhibitors of CYP3A4 (eg, ketoconazole). Inducers of CYP3A4 (eg, rifampin) increase the hepatic metabolism of eszopiclone.

Question 42

How are sedative-hypnotic drugs eliminated?

Answer 42

The water-soluble metabolites of sedative-hypnotics, mostly formed via the** conjugation of phase I metabolites**, are excreted mainly via the **kidney**.

Question 43

In most cases, **changes in renal function** do not have a marked effect on the elimination of parent drugs.

Answer 43

So if may kidney prob not affected ang elimination ng sedative-hypnotic drugs

Question 44

**Phenobarbital** is excreted **unchanged in the urine** to a certain extent **(20–30**% in humans), and its **elimination rate** can be increased significantly by \_\_\_\_\_\_\_\_\_\_. This is partly due to **increased ionization** **at alkaline pH,** since **phenobarbital is a weak acid** with a pK a of 7.4.

Answer 44

alkalinization of the urine

Question 45

What are the factors affecting the biodisposition of sedative-hypnotic drugs?

Answer 45

The biodisposition of sedative-hypnotics can be influenced by several factors, particularly **alterations in hepatic function** resulting from **disease or drug-induced increases or decreases in microsomal enzyme activities** (see Chapter 4 ).

Question 46

In very old patients and in patients with severe liver disease, the **elimination half-lives** of these drugs are often increased significantly. In such cases, **multiple normal doses** of these sedativehypnotics can result in **\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

Answer 46

**excessive central nervous system effects.**

Question 47

The **activity of hepatic microsomal drug-metabolizing enzymes** may be **increased in patients exposed** to certain older sedativehypnotics on a **long-term basis** (enzyme induction; see Chapter 4 ). \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ are most likely to cause this effect, which may result in an **increase in their own hepatic metabolism**as well as that of other drugs. Increased biotransformation of other pharmacologic agents as a result of enzyme induction by barbiturates is a potential mechanism underlying drug interactions (see Chapter 66 )

Answer 47

Barbiturates (especially phenobarbital) and meprobamate

Question 48

. In contrast, **\_\_\_\_\_\_\_\_\_\_\_ and \_\_\_\_\_\_\_\_\_\_** **do not change hepatic drug-metabolizing enzyme activity**with**continuous use.**

Answer 48

**benzodiazepines** and the **newer hypnotics**