Sedatives i.e. Anxiolytics

Question 1

What are the 4 classes of sedatives?

Answer 1

CLASS 1) Anti-depressants
CLASS 2) Benzodiazepines (diazepam, lorazepam, clonazepam, alprazolam)
CLASS 3) Buspirone
CLASS 4) Beta-blockers (propanolol, atenolol)

Question 2

What type of regimen is most successful for sedative and hypnotic administration?

Answer 2

NON-CHRONIC, SHORT-TERM REGIMEN - Pharmacological treatment of sedatives and hypnotics must be short-term, as depicted by the anxiety state (due to many disadvantages)

Question 3

What is the gradient of CNS depression?

Answer 3

1) Sedation
2) Hypnosis
3) Anesthesia
4) Coma

Question 4

What is the general goal of a prescribed dose of sedatives?

Answer 4

Find the LOWEST dose that achieves the calming, anti-anxiety effect WITHOUT impairing psychomotor function (mentation and motor abilities)

Question 5

CLASS 2 BZ) Name the 2 pharmacokinetic properties of BZs.

Answer 5

1) Rapid onset (high lipophilicity)

2) Long half-life

Question 6

CLASS 2 BZ) Name the two contra-indications of BZ usage.

Answer 6

1) Pregnant women - Due to BZs high lipophilicity, it can cross the BBB as well as the placental barrier and depress neonatal vital functions
2) Child-rearing mothers who breastfeed - Detectable in breast milk

Question 7

CLASS 2 BZ) Name the pharmacodynamic mechanism of BZs (e.g. diazepam, clonazepam, alprazolam, etc.)

Answer 7

Binds to molecular components of the GABA-R -> Increases the frequency of Cl- channel opening -> Increases hyperpolarization -> Decreases CNS excitability = GABAergic inhibition

Question 8

CLASS 2 BZ) Which drug is highly effective for a BZ overdose? What is its mechanism of action?

Answer 8

FLUMAZENIL - BZ competitive antagonist

Question 9

CLASS 2 BZ) Name the #1 use of BZs. Name 4 advantages pertaining to this usage.

Answer 9

ACUTE ANXIETY ATTACKS (e.g. panic attacks)

1) Rapid onset
2) Relatively high therapeutic index + availability of FLUMAZENIL in case of an overdose
3) Low risk of drug interactions based on liver enzyme induction
4) MINIMAL hemodynamic (CV) or autonomic effect

Question 11

CLASS 2 BZ) What is the graphical representation of how BZs and newer hypnotic agents came to replace Barbiturates (BRs)?

Answer 11

BZs - Non-linear, plateau graded dose-dependent CNS depression: SAFE bec a large, directly proportional increase in dosage will NOT result in severe CNS depression (anesthesia, coma)

BRs - Linear graded dose-response curve: DANGEROUS bec a large, directly proportional increase in dosage can induce anesthesia and higher than hypnotic doses can induce COMA

Question 11

CLASS 2 BZ) Name the 4 severe disadvantages of BZ usage.

Answer 11

1) Risk of DEPENDENCE - both psychological + physiological
2) CNS Depressive Effects - Additive (esp when pt is taking anti-histamines, anti-cholinergic, and ethanol)
3) Amnesic effects
4) Predilection for dis-inhibition behaviors

Question 12

CLASS 2 BZ) Dosing Consideration - What is the general rule for prescribing BZs to the elderly? Why?

Answer 12

Prescribe half the dose of the normal young adult dosage

Reason - They’re particularly sensitive due to poor clearance -> Drug can accumulate to toxic levels

Question 13

CLASS 2 BZ) Dosing considerations - What medications should be advised against when taking an anxiolytic?

Answer 13

Other CNS depressants - anti-cholinergics + anti-histamines + ethanol

Question 14

CLASS 2 BZ) Other Therapeutic Side Usages: Name the 4 other usages.

Answer 14

1) Sedative/Amnesic Effect during medical or surgical procedures
2) Anesthesia
3) Muscle Relaxation
4) Management of Seizures

Question 15

CLASS 2 BZ) Other Therapeutic Usages: What is the BZ used as a sedative/amnesic during medical or surgical procedures? What pharmacokinetic property facilitates this usage?

Answer 15

MIDZOLAM - Useful for endoscopy and bronchoscopy or pre-medication prior to anesthesia
SHORT HALF-LIFE makes this desirable for such procedures

Question 16

CLASS 2 BZ) Other Therapeutic Uses: Which BZ is used to treat muscle spasms?

Answer 16

DIAZEPAM - Neuronal depressive effects are not only exerted on CNS, but also control CNS muscles

Question 17

CLASS 2 BZ) Other Therapeutic uses: Which BZs (2) are used as adjuncts for general anesthesia? What is the route of administration?

Answer 17

DIAZEPAM + LORAZEPAM (via IV and never used alone)

Question 18

CLASS 2 BZ) Other Therapeutic Uses: Which BZs (3) are used to manage seizures?

Answer 18

DIAZEPAM + LORAZEPAM + CLONAZEPAM - Sufficiently selective enough to exert anti-convulsive and sedative effects w/o marked CNS depression

Question 19

CLASS 2 BZ) CLINICAL TOXICOLOGY: What are the (4) DIRECT CNS Toxic Effects of BZ?

Answer 19

1) DECREASED psychomotor ability (impaired judgment, mentation, motor abilities)
2) DOSE-DEPENDENT Anterograde Amnesia - Inability to LEARN new memories + RETAIN new material
3) ELDERLY - confusional state (not good to conforming to physician’s orders even though 1/2 the dose is prescribed)
4) HIGH DOSES - Lethargy or state of exhaustion (as in severe alcohol intoxication)

Question 20

CLASS 2 BZ) CLINICAL TOXICOLOGY: What are the DIRECT CV and respiratory effects of BZ?

Answer 20

HEALTHY PTS (normal hypnotic doses): Respiratory depression (as in sleep), NO (minimal) CV effects

DISEASED PTS (pulm/cardio diseases = sensitive pts): SIGNIFICANT respiratory + CV depression

Question 21

CLASS 2 BZ) CLINICAL TOXICOLOGY: After the dvlm of tolerance and dependence post-prolonged BZ usage, what are the 3 withdrawal symptoms?

Answer 21

1) INCREASED REBOUND HYPER-ANXIETY - a toxic side-effect that immediately goes against why the pts started taking the BZs
2) Insomnia, headaches
3) Increased CNS excitability can result in CONVULSIONS, if super-physiologically affected

Question 22

CLASS 2 BZ) CLINICAL TOXICOLOGY: What is the #1 worry of a BZ overdose? How can this be complicated?

Answer 22

#1 worry = RESPIRATORY DEPRESSION
Further complicated by potential pulmonary aspiration of gastric contents (very likely with ethanol intoxication)

Question 23

CLASS 2 BZ) CLINICAL TOXICOLOGY: What are the two required modes of treatment after a BZ overdose?

Answer 23

1) IV DRUG FLUMAZENIL - BZ competitive antagonist that has very rapid onset and will immediately reverse CNS depressant effects of BZ overdose
2) KEEP A PATENT AIRWAY - Airway is so depressed that patent airway is necessary + ventilator if necessary to maintain plasma volume, renal output and cardiac function

Question 24

CLASS 2 BZ) CLINICAL TOXICOLOGY: What are the two disadvantages of FLUMAZENIL adminstration after a BZ overdose (*Hint: What happens to withdrawal symptoms?)

Answer 24

1) Short half-life (0.7-1.3hrs): CNS Depression effects are reversed but 2hrs later, pts feel lethargic again -> Requires REPEATED administration
2) When there is addiction (tolerance + psychological/physiological dependence), the withdrawal symptoms will resurface

Question 25

CLASS 2 BZ) CLINICAL TOXICOLOGY: When a pt suffers through acute BZ withdrawal symptom, what is the method of treatment?

Answer 25

Slowly taper the pt off with longer half-life BZs: Process may take a while

Question 26

CLASS 3 BUSPIRONE) What makes this drug unique to all other sedatives?

Answer 26

It does NOT target the GABA system -> CNS depression is less (no impairment of mental state), while achieving a calming effect

Question 26

CLASS 3 BUSPIRONE) What is the “proposed” mechanism of buspirone (still unclear in literature)

Answer 26

Potential Targets: Agonizes the SEROTONIN (5-HT1A) receptors + has an affinity for the brain DOPAMINE (D2) receptors

Question 27

CLASS 3 BUSPIRONE) What are the 3 advantages of this drug?

Answer 27

1) LESS CNS depression - unimpaired mental state
2) LESS dependence - Can be administered for a LONGER period of time bec risk of dependence is LOW and the drug is NOT GABAergic
3) NO Rebound anxiety or Withdrawal signs on abrupt discontinuance

Question 28

CLASS 3 BUSPIRONE) If a pt is undergoing BZ withdrawal, can we use buspirone to treat the withdrawal?

Answer 28

NO

Buspirone willl NOT substitute for BZ upon abrupt BZ cessation resulting in withdrawal

Question 29

CLASS 3 BUSPIRONE) What is the #1 usage of buspirone now? Why?

Answer 29

Generalized Anxiety Disorders - Slower half-life

Buspirone may take 1-2 weeks to become established

Question 30

CLASS 3 BUSPIRONE) What are 3 major disadvantages

*Hint - half-life, effect on body systems, drug interactions

Answer 30

1) Half-life is longer -> Anxiolytic effects of buspirone take about 1-2 weeks to be established -> Would NOT use in acute anxiety states such as panic attacks
2) Effect on systems: TACHYCARDIA, tinnitus, GI distress, parathesia (tinglings)
3) HIGH risk of drug interactions based on CYP3A4 induction and inhibition (>50% of drugs are metabolized by CYP3A4)

Question 31

CLASS 4 BETA-BLOCKERS) What are the two beta blockers used as an off-label application for treating anxiety?

Answer 31

1) Propanolol (Inderal)

2) Atenolol (Tenormin)

Question 32

CLASS 4 BETA-BLOCKERS) What does it mean for the beta-blockers to be off-label?

Answer 32

Strictly treating the SYMPTOMS of anxiety (trembling, profuse sweating) - people who need to be in public but have anxiety