ANXIOLYTICS, SEDATIVES AND HYPNOTICS Flashcards
Describe CENTRAL GABA-MEDIATED INHIBITION
- short axon GABA interneurones in the brain –> has regulatory role
- keep firing rates within certain parameters
Glutamate = precursor for GAB
GLU –> converted to GABA (via GAD)
- GABA = stored in vesicle in presynaptic terminal
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Describe the synthesis of GABA
Glutamate = precursor for GAB GLU --> converted to GABA (via GAD) - GABA = stored in vesicle in presynaptic terminal - until depolarization occurs - VGCC opens - Causes exocytosis
- chloride flows into post synaptic cell –> causes hyperpolarisation
Describe the metabolism of GABA
- GABA = converted to –> Succinic semialdehyde (SSDH)
- via GABA- Transaminase - SSDH = converted to –> Succinic Acid
- via succinic semialdehyde dehydrogenase
Succinic Acid - goes back o TCA Cycle
NOTE:
GABA-T + SSDH = Mitochondrial enzymes
- Inhibitors of GABA Metabolism leads to large accumulation of Brain GABA
Anticonvulsive drugs:
- SODIUM VALPROATE (EPILIM)
- -> SSDH + GABA T inhibitor
- VIGABATRIN (SABRIL)
Describe the reuptake of GABA
- primary inactivation method of GABA
- uptake into glial cells / presynaptic cells
- GABA –> converted to SSA (Via GABA-T)
describe the structure of the GABAa receptor complex
- GABA receptor protein
- Barbiturate receptor protein
- BDZ receptor protein
- chloride channel protein
GABAA receptor complex: (post-synaptic) 4 main proteins (not inc. modulin)
- GABA binds GABA receptor protein à links w/ BDZ receptor protein mediated by GABA modulin à opens Cl- channel proteins
- If BDZ binds BDZ receptor protein à enhances GABA action on Cl- channel
o Also, binding/affinity of GABA is enhanced
o This is reciprocal: binding of GABA enhances affinity of BDZ too
- BARB enhances GABA action at Cl- channel + GABA affinity (not reciprocal)
o At high doses, BARBs directly stimulate Cl- channel
- Triangle = Bicuculline is competitive GABAA receptor antagonist
- Rectangle = Flumazenil is competitive BDZ antagonist
how do Bz + Barbs similar / differ
SIMILARITY:
- No activity alone b/c work by enhancing GABA (allosteric action
DIFFERENCE:
- -> Different binding sites + mechanisms:
- BZs increase frequency of openings (same duration)
- BARBs increase duration of openings (no frequency change)
–> BARBs = less selective than BZs
o Cause decreased excitatory transmission
o Other membrane effects e.g. at high doses
o May explain why:
- BARBs can induce surgical anaesthesia (BZs can’t do this)
- BARBS have low margin of safety
What are some clinical uses of BZs + BARBS ?
ANAESTHETICS (BARBs ONLY : THIOPENTONE)
ANTICONVULSANTS (DIAZEPAM; CLONAZEPAM; PHENOBARBITAL)
ANTI-SPASTICS (DIAZEPAM)
ANXIOLYTICS
SEDATIVES / HYPNOTICS
define anxiolytics
anxiolytics : REMOVE ANXIETY WITHOUT IMPAIRING MENTAL OR PHYSICAL ACTIVITY
Define sedatives
SEDATIVES: REDUCE MENTAL AND PHYSICAL ACITVITY WITHOUT PRODUCING LOSS OF CONSCIOUSNESS
Define Hypnotics
HYPNOTICS: INDUCE SLEEP
BZ + BARBS clinically
IDEALLY: THEY SHOULD:
i) HAVE wide / narrow MARGIN OF SAFETY
ii) depress / not depress RESPIRATION
iii) produce/ do not produce NATURAL SLEEP (HYPNOTICS)
iv) interacts / doest interact WITH OTHER DRUGS
v) produces / doesn’t produce ‘HANGOVERS’
vi) produces / doesn’t produce DEPENDENCE
- IDEALLY: THEY SHOULD:
i) HAVE WIDE MARGIN OF SAFETY
ii) NOT DEPRESS RESPIRATION
iii) PRODUCE NATURAL SLEEP (HYPNOTICS)
iv) NOT INTERACT WITH OTHER DRUGS
v) NOT PRODUCE ‘HANGOVERS’
vi) NOT PRODUCE DEPENDENCE
What are clinical uses of barbiturates?
what is half life of barbiturates
- sedative / hypnotic
- -> Amobarbital
- -> severe intractable insomnia
- -> Half life = 20 - 25hrs
What are unwanted effects of barbiturates?
- DEPRESS RESPIRATION
- OVERDOSING = LETHAL
- alters natural sleep (decreases REM) –> Hangovers / Irritability
- potentiates effects of other CNS Depressants e.g alcohol
- enzyme inducers
- tolerance development
- withdrawal syndrome (insomnia, anxiety, tremor, convulsions, death)
Describe the pharmacokinetics of Benzodiazepines
- PEAK [PLASMA] ~ 1h
- binds to plasma proteins strongly
- highly lipid soluble
- metabolized extensively in liver
- excreted via urine (glucuronide conjugates)
Benzodiazepines –> ALL act at GABAa receptors
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What are the 2 types of
SHORT-ACTING
e.g temazepam, oxazepam
LONG-ACTING
–> tends to have slower METABOLISM
+ ACTIVE METABOLITES
e.g diazepam , nor diazepam
Longer acting benzodiazepines are usually used as =
ANXIOLYTICS
Short acting benzodiazepines are suavely used as =
SEDATIVE / HYPNOTICS
What are advantages of Bezodiazepines?
- WIDE MARGIN OF SAFETY
OVERDOSE –> PROLONGED SLEEP (but ROUSABLE)
-IV FLUMAZENIL –> treats BZ overdose - MILD EFFECT ON REM SLEEP
- DO NOT INDUCE LIVER ENZYMES
What are unwanted effects of benzodiazepines?
SEDATION, CONFUSION, AMNESIA,ATAXIA (IMPAIRED MANUAL SKILLS)
POTENTIATE OTHER CNS DEPRESSANTS (ALCOHOL; BARBs)
TOLERANCE (LESS THAN BARBs; ‘TISSUE’ ONLY)
DEPENDENCE:
- WITHDRAWAL SYNDROME SIMILAR TO BARBs (LESS INTENSE)
- -> WITHDRAW SLOWLY
- FREE [PLASMA] increases BY e.g. ASPIRIN, HEPARIN
what are some other drugs used as sedatives / hypnotics ?
ZOPICLONE
- ->SHORT ACTING (t½ ~ 5h)
- -> ACTS AT BZ RECEPTORS (CYCLOPYRROLONE)
- ->SIMILAR EFFICACY TO BZs
- -> MINIMAL HANGOVER EFFECTS BUT DEPENDENCY STILL A PROBLEM
what are some other drugs used as anxiolytics?
- some anti depressant drugs
SSRIs (see PT 16; Dr Croucher)
LESS SEDATION & DEPENDENCE / DELAYED
RESPONSE / LONG-TERM TREATMENT - some anti epileptic drugs
e. g valproate, tiagabine - some antipsychotic drugs
e. g. OLANZAPINE, QUETIAPINE - Propranolol
- -> IMPROVES PHYSICAL SYMPTOMS
- TACHYCARDIA (b1)
- TREMOR (b2)
- Buspirone
- 5HT1A AGONIST
- FEWER SIDE-EFFECTS (< SEDATION)
- SLOW ONSET OF ACTION (DAYS / WEEKS)
Benzodiazepines are used to treat ‘panic attacks’ and other anxiety states. By what mechanism do they produce their anti-anxiety effects?
A: Inhibition of GABA breakdown
B: Activation of 5HT1A receptors
C: Enhancement of the action of GABA at GABA-A receptors
D: Inhibition of GABA reuptake
E: Enhancement of the action of GABA at GABA-B receptors
C: Enhancement of the action of GABA at GABA-A receptors
Which of the following drugs is commonly used in the treatment of insomnia?
A: Thiopental B: Phenytoin C: Baclofen D: Sodium valproate E: Temazepam
E: Temazepam
