Sedative-Hypnotics and Anxiolytics

15. Distinguish between the terms "tolerance" and "dependence" (Drugs of Abuse, LO1) and associate these two terms to the use of benzodiazepines and barbiturates

Drug tolerance -is a pharmacology concept where a subject's reaction to a specific drug and concentration of the drug is reduced followed repeated use, requiring an increase in concentration to achieve the desired effect. -toxicity and lethality often do not shift, so overdose is more likely Substance dependence (sort of encompasses tolerance) -also known as drug dependence is an adaptive state that develops from repeated drug administration, and which results in withdrawal upon cessation of drug use -drug craving / drug seeking behavior (psychological)

14. Describe the mechanism of action of flumazenil and apply it to a clinical scenario

Flumazenil, a *benzodiazepine antagonist*, binds to a similar site occupied by benzodiazepines and ZZZ agents and can be used as *antidote in situations of overdose* for those two classes of agents flumazenil is *not effective for barbiturate overdose*

2. Compare and contrast structures, pharmacodynamics features, and function of GABAA and GABAB receptors

GABA-A -pentameric transmembrane glycoproteins forming a central ion pore (sensitive to Cl-) -2 GABA molecules required to bind to receptor -Porlonged occupation of agonist sites leads to receptor desensitization (transition to inactive agonist bound state) GABA-B -G-protein coupled, expressed at lower levels than GABA-A -found mainly in spinal cord -K+ channels -found presynaptically and post-synaptically -slower activation and deactivation compared to GABA-A

23. Discuss the mechanism of action of baclofen and apply it to a clinical scenario

GABA-B receptor agonist -muscle relaxant

24. buspirone = apply its mechanism of action to a clinical scenario

Partial agonist of 5-HT1-A receptors Indication: Generalized anxiety -However, takes more than a week for anxiolytic effect to establish, so it is not effective for management of acute anxiety attacks

19. Identify the only barbiturate for refractory (stubborn or unmanageable) epilepsy

phenobarbital?

10. Based on the effect of benzodiazepines on the sleep cycle, discuss the usefulness of benzodiazepine as a treatment of insomnia

Benzodiazepines and barbiturates can alter sleep architecture -increase length of stage 2 (NREM - the light sleep that normally makes up half the sleeping time) -Suppress slow wave/deep sleep (stage 3&4) and REM sleep (frequent dream period)

6. Explain why benzodiazepine use should be intermittent

Benzodiazepines and barbiturates can cause tolerance and physical dependence when used for a long period of time = due to receptor desensitization / downregulation due to prolonged enhancement

3. Differentiate between the safety profile for benzodiazepines and barbiturates (see addendum ii)

-At high doses and when used alone, benzodiazepines can cause hypnosis but rarely causes fatal CNS depression -In contrast, barbiturates/alcohol display a linear dose-response effect that progresses to severe CNS depression, leading to respiratory depression, coma, and death. This is the reason why the *clinical uses of barbiturates have been increasingly replaced with benzodiazepines*

16. Describe the mechanism of action of barbiturates and indicate how they affect the activity of GABA-A receptors

-Barbiturates bind to GABA-A receptor, which is a Cl- ion channel activated by endogenous γ-aminobutyric acid (GABA) -Barbiturates bind distinctly at another site on receptor (allosteric) -Barbiturates *increase duration* of GABAA channel opening, AND at higher conc., can *directly activate chloride channels*

12. Discuss the metabolism of benzodiazepines and predict situations where drug-drug interaction may occur -Metabolites of (3?) are *short-acting*

-Metabolites of midazolam, alprazolam, and triazolam are *short-acting*

12. Discuss the metabolism of benzodiazepines and predict situations where drug-drug interaction may occur -Metabolites of (3?) are *long-acting*

-Most are metabolized by phase I CYP enzymes to active metabolites -Metabolites of chlordiazepoxide, diazepam, and flurazepam are *long-acting*

12. Discuss the metabolism of benzodiazepines and predict situations where drug-drug interaction may occur do not have metabolites and are directly conjugated for elimination (3?)

-Oxazepam, temazepam, and lorazepam do not have metabolites and are directly conjugated for elimination (Out ThE Liver) -Since phase II biotransformation is less likely to be affected by hepatic insufficiency, this group of agents is more useful for elderly individuals or people with reduced liver function

18. List four clinical uses of barbiturates

-Sedative (anxiolytic) -hypnotic (insomnia) -seizures -induction of anesthesia (thiopental)

7. List six clinical uses of benzodiazepines

-Sedative (anxiolytic), hypnotic (insomnia) -Preoperative anesthesia (amnesia, muscle relaxation) -Induction of anesthesia (midazolam) -Status epilepticus (lorazepam, diazepam) -Alcohol detoxification -Night terrors

1. Define "sedative" and "hypnotic" (see addendum i)

-Sedative is also commonly referred as anxiolytic, through its effect to calm and reduce anxiety -Hypnotic describes the ability to induce drowsiness and cause sleep. Hypnotic effects involve more pronounced depression of the CNS than sedation. -Both sedation and hypnosis are graded, dose-dependent responses to depression of CNS function. Low doses will cause sedation, and at higher doses the responses become hypnosis, the medical term for sleep -Note that there are agents (eg buspirone) that are anxiolytic but do not produce either sedation or hypnosis, hence the name: anxiolytics

8. Identify two benzodiazepines indicated for status epilepticus

-Status epilepticus (*lorazepam, diazepam*)

22. Discuss the contraindication of barbiturates (see addendum vii) what the heck is porphyria?

-The body requires porphyrins to produce heme, which carries oxygen in the blood -in the porphyrias, there is a deficiency (inherited or acquired) of the enzymes that transform the various porphyrins into others, leading to abnormally high levels of one or more of these substances. This manifests with neurological symptoms or skin problems, or occasionally both -Patients with porphyria usually presents with abdominal pain, localized tenderness, blistering lesions on sun-exposed skin, and red-wine colored urine.

13. Describe the adverse effects in relations to therapeutic effects of benzodiazepines Side Effects

-Tolerance and dependence -CNS depression Less than barbiturates Overdose can be treated with flumazenil

22. Discuss the contraindication of barbiturates (see addendum vii)

-barbiturates are absolutely contraindicated in patients with porphyria -Barbiturates induce the rate-limiting enzyme in porphyrin biosynthesis, α-aminolevulinate synthase, and may exacerbate porphyria, a condition in which a hereditary defect causes excessive porphyrin synthesis and excretion, which causes neurologic and cutaneous adverse effects

5. Describe the mechanism of action of benzodiazepines and indicate how they affect the activity of GABAA receptors

-bind to GABAA receptor, which is a Cl- ion channel activated by endogenous γ-aminobutyric acid (GABA) -Benzodiazepine binding site is in between α and γ subunits -Benzodiazepines increase the frequency of GABA-A channel opening -Benzodiazepines (and ZZZ agents) do not have effects in the absence of GABA

11. Compare the effectiveness of zolpidem, zaleplon, and eszopiclone with benzodiazepine for the treatment of insomnia (see addendum v)

The newer agents non-benzodiazepines zolpidem, zaleplon, and eszopiclone have largely replaced older benzodiazepines for the treatment of insomnia -The advantages of these agents over benzodiazepines include: 1. Lack of effect on REM or slow-wave sleep 2. Less potential for tolerance and dependence 3. Shorter duration of action, which precludes daytime sedation and hangover effects -These advantages are due to the ability of these agents to *selectively act on GABA-A receptors that contain α1 subunits (BZ1 subtype)*

21. Discuss the effects of chronic barbiturate use and predict situations where drug-drug interaction may occur

-chronic use leads to tolerance and physiological dependence, why> prolonged use increase P450 enzyme activity and accelerates barbiturate metabolism -physiologic dependence leads to drug withdraw syndrome = tremors, anxiety, insomnia, and CNS excitability

17. Based on its mechanism of action, discuss why barbiturate overdose is dangerous

-follow a linear dose-response and higher doses can lead to Severe CNS depression (anesthesia) and eventually depress respiratory and vasomotor centers, leading to death

21. Discuss the effects of chronic barbiturate use and *predict situations where drug-drug interaction may occur*

? - I would guess increased P450 enzyme activity could render other drugs the patient takes less effective or toxic (active form vs. pro-drug respectively)

4. Describe the basis for clinical situations where levels of benzodiazepines may be increased and identify benzodiazepines that may best be used in those situations based on their metabolism and duration of action (see addendum iii) maybe OTLs to be kind to the liver? or switch from short acting to long acting metabolites = I don't know this one

*Chlordiazpoxide, diazepam, and flurazepam* are converted to long-acting active metabolites. Alprazolam, midazolam, and triazolam are converted to short-acting active metabolite. All benzodiazepines, including those with no active metabolites, eventually go through glucuronidation reaction to yield inactive metabolites for renal excretion. Oxazepam, temazepam, and lorazepam ("out the liver") are three benzodiazepines that do not undergo phase I metabolism and are directly conjugated before renal excretion. For this reason, these three benzodiazepines may be the safest to use for elderly patients or other patients with reduced liver function.

9. Identify the only benzodiazepine indicated for induction of anesthesia (see addendum iv)

*Midazolam is the only benzodiazepine currently indicated for induction of anesthesia* (General Anesthesia, addendum iv) Lorazepam and diazepam are currently NOT indicated for general anesthesia, but are instead given as a medication before surgery for their sedative and anterograde amnesia effects. Statements in the textbook about lorazepam and diazepam being used for IV general anesthesia are incorrect.

20. Identify the barbiturate more commonly used for induction of anesthesia (see addendum vi)

*Thiopental* is currently the more commonly used barbiturate indicated for induction of anesthesia. Using this barbiturate for maintenance is not recommended due to its long context-sensitive half-time (General Anesthesia: addendum iv). Methohexital is indicated for anesthesia, but due to its ability to induce seizures, thiopental is more commonly used. Pentobarbital is mostly used as an adjunct to anesthesia.

24. Discuss the advantages of buspirone over benzodiazepines

Relieves anxiety without sedative, hypnotic effects -No abuse potential -No anticonvulsant or muscle relaxant properties