Anxiolytic, Sedative and Hypnotic Drugs-part 1

Question 1

Why would you want to use oxazepam for anxiety

Answer 1

For patients with hepatic impairment. Thier enzymes do not work as effeciently , increasing th etime for metabolism so the drug becomes even more long acting. So you ewould use this has it is more short acting than other anxiolytics,

Question 2

What are barbiturates mainly used for,Give an example and the specifc case when you would se it with it;s half life information

Answer 2

Question 3

Explain the GABA A receptor complex

Answer 3

Cl- ionophores - cause hyperpolarisation: GABA modulin + GABA R protein + Barbiturate R protein + BDZ R protein in ring with Cl- channel protein in middle

Question 4

How is GABA metabolised?

Answer 4

GABA –> succinic semialdehyde (SSA) by GABA transaminase SSA –> succinic acid by SSA dehydrogenase Mitochondrial enzymes

Question 5

How do barbiturates and benzodiazepines differ?

Answer 5

• Different binding sites and mechanisms: BZs increase frequency of openings, barbs increase duration, opening caused by GABA - Barbs are less selective - other membrane effects, decrease excitatory transmission (may explain induction of surgical anaesthesia and low margin of safety)

Question 6

Why do the pharmacokinetics of benzodiazepines determine clinical use?

Answer 6

• 20+ different benzodiazepines with very small differences in structure (3 rings, differ in R1, R2, R3, R4) - Same mechanisms of action - Similar potency - Tf pharmacokinetics determine clinical use

Question 7

How does Barb binding affect the GABA A receptor complex?

Answer 7

• Enhances GABA binding( GABA is a Direct agonist of Cl- channel ). Enhances GABA action on Cl- channel

Question 8

What do sedatives do?

Answer 8

Reduce mental and physical activity without producing loss of consciousness

Question 9

What do anxiolytics do?

Answer 9

Remove anxiety without impairing mental or physical activity

Question 10

What makes nitrazepam differe from other SEDATIVE / HYPNOTICS Why would you want to use NITRAZEPAM for sedation?

Answer 10

Nitrazepam is long-acting .If you want anxioltyic effect along side the the sedative effect , like particularly in daytime.

Question 11

What are the adverse effects of benzodiazepines?

Answer 11

• Dependence : withdrawal syndrome (less intense than barbs) .

Tolerance (less than barbs)

Potentiate other CNS depressants (alcohol, barbs) - Sedation, confusion, amnesia, ataxia

Question 12

Summarise the pharmacokinetics of benzodiazpepines

Answer 12

• Duration of action - varies - short or long-acting - Admin - peak [plasma] in 1h, well-absorbed orally, i.v. for status epilepticus - Distribution - binds PPs strongly, highly lipid soluble –> wide distribution - Extensive hepatic metabolism

Question 13

For other OTHER SEDATIVE/HYPNOTICS:

Recall information on:

,HANGOVER EFFECTS ,Half life, recpetors they act on,EFFICACY,DEPENDENCY

Answer 13

ZOPICLONE

•SHORT ACTING (t½ » 5h)

ACTS AT BZ RECEPTORS (CYCLOPYRROLONE)

• SIMILAR EFFICACY TO BZs
• MINIMAL HANGOVER EFFECTS BUT

DEPENDENCY STILL A PROBLEM

Question 14

Why do benzodiazepines and barbiturates have no activity alone?

Answer 14

They are positive allosteric modulators Only increase freq or duration of opening caused by GABA

Question 15

Describe the metabolism of benzodiazepines

Answer 15

Only remember boxed one for now

Question 16

What do hypnotics do?

Answer 16

Induce sleep

Question 17

What would an ideal benzodiazepine or barbiturate do?

Answer 17

• Produce natural sleep , Not depress respiration , Have a wide margin of safety ,Not produce hangovers or dependence , Not interact with other drugs

Question 18

What receptor is involved in GABAergic central neurotransmission?

Answer 18

GABA A receptor complex

Question 19

What are benzodiazepines mainly used for,Give an example s

Answer 19

Question 21

What are the adverse effects of barbiturates?

Answer 21

-Enzyme inducers ,Alter natural sleep (reduce REM) –> hangover, irritability , Depress respiration and O.d. is lethal(tf low safety margins) , Dependence (withdrawal syndrome) , Tolerance -,Potentiate effects of other CNS depressants (alcohol)w

Question 22

What drugs can increase free [plasma] of benzodiazepines?

Answer 22

Aspirin Heparin

Question 23

What are the advantages of benzodiazepines over barbiturates?

Answer 23

• Mild effect on REM sleep , Don’t induce liver enzymes , Wide safety margin . overdose –> prolonged rousable sleep –> flumazenil

Question 24

How does GABA binding affect the GABA A receptor complex?

Answer 24

• Linkage of GABA receptor protein and BDZ receptor protein mediated by GABA modulin - Enhances BDZ binding - Momentary opening of Cl- channel

Question 25

How does BDZ binding affect the GABA A receptor complex?

Answer 25

• Facilitates action of GABA on Cl- channel - Enhances GABA binding - increases affinity

Question 26

How is GABA synthesised?

Answer 26

Glutamate –> GABA by glutamate decarboxylase

Question 27

What are the clinical uses of benzodiazepines and barbiturates?

Answer 27

• Sedatives/hypnotics , Anti-spastics,
• ANAESTHETICS (BARBs ONLY : THIOPENTONE)
• ANTICONVULSANTS (DIAZEPAM; CLONAZEPAM; PHENOBARBITAL)
• ANTI-SPASTICS (DIAZEPAM)

Question 28

Recall inhibitors of GABA metabolism and the consequences of their actions

Answer 28

•

• INHIBITORS OF GABA METABOLISM causes LARGE increase in ­ BRAIN GABA
• SODIUM VALPROATE (EPILIM)
• VIGABATRIN (SABRIL)

Question 29

For OTHER named SEDATIVE/HYPNOTICS, comment on :

t½ ,RECEPTORS it acts on, efficacy ,HANGOVER EFFECTS and DEPENDENCY

Answer 29

ZOPICLONE

• SHORT ACTING (t½ » 5h)
• ACTS AT BZ RECEPTORS (CYCLOPYRROLONE)
• SIMILAR EFFICACY TO BZs
• MINIMAL HANGOVER EFFECTS BUT

DEPENDENCY STILL A PROBLEM

Question 30

Give informatoin on OTHER named ANXIOLYTICS

Answer 30

SOME ANTIDEPRESSANT DRUGS

•SSRIs(LESS SEDATION & DEPENDENCE / DELAYED

RESPONSE / LONG-TERM TREATMENT)

_SOME ANTIEPILEPTC DRUGS(_e.g. VALPROATE, TIAGABINE)

_SOME ANTIPSYCHOTIC DRUGS(_e.g. OLANZAPINE, QUETIAPINE)

PROPRANOLOL

•IMPROVES PHYSICAL SYMPTOMS

ØTACHYCARDIA (b1)

ØTREMOR (b2)

BUSPIRONE

5HT1A AGONIST

FEWER SIDE-EFFECTS (< SEDATION)

SLOW ONSET OF ACTION (DAYS / WEEKS)