HL: PDA III Exam I - GABAergic Anxiolytics LOs

What is anxiety?

fear, apprehension, or dread of impending danger accompanied by restlessness, tension, tachycardia, and dyspnea unattached to a clearly identifiable stimulus

What is an axiolytic?

anti-anxiety agent

What is a sedative?

agent that quiets nervous excitement

What is a hypnotic?

agent that promotes sleep

What is gamma aminobutyric acid (GABA)?

the primary inhibitory neurotransmitter (NT) in the brain

blocks impulses between nerve cells

What is GABA primarily synthesized from?

glutamate by glutamic acid decarboxylase (GAD)

Where is GABA released?

into the synaptic cleft when the presynaptic neuron depolarizes

True or False: GABA binds with postsynaptic GABA receptors

True

True or False: GABA may be transported back into presynaptic neuron via re-uptake channels

True

Explanation: GABA is inactivated by GABA aminotransferase (GABA-T) → succinate OR to be stored in vesicles

What is GABAergic?

agent that enhances GABA's activity

True or False: glutamate is an inhibitory NT

False

Explanation: glutamate is excitatory, and GABA is inhibitory

True or False: GABA-A receptor channels are formed from protein subunits

True

True or False: GABA-A receptors are ligand-gated, ionotropic, and allosteric

True

Explanation: ligand-gated channels open when GABA ligand binds to receptors, inotropic channel allows ions to pass through when GABA binds to receptors, allosteric modulation of GABA-A at various sites

True or False: most medication classes have distinct sites that differ from GABA

True

Explanation: for example, benzos bind to the same site BUT the site is distinct from binding sites for barbiturates, neurosteroids, or GABA

What is GABAergic effect of GABA-A receptors?

when bound to GABA-A, some meds enhance Cl influx that occurs when GABA also binds to GABA-A

What is BZRA of GABA-A receptors?

meds that bind at the benzo binding site of GABA-A are benzo receptor agonists

What is an anxiety disorder?

disorder in which anxiety impairs normal daily functioning

What are types of anxiety disorders?

Generalized Anxiety Disorder (GAD),

Panic Disorder,

Agoraphobia,

Social Anxiety Disorder (SAD),

Post-Traumatic Stress Disorder (PTSD),

Obsessive Compulsive Disorder (OCD),

Specific Phobia

What is panic disorder?

unexpected and repeated panic attacks

What is agoraphobia?

extreme or irrational fear of crowded spaces or enclosed public places that are often triggered by a panic attack

What are causes of anxiety disorders?

3 Models:

1. noradrenergic

2. GABA receptor

3. serotonin 5-HT

What is the noradrenergic model of anxiety disorders?

ANS is over reactive to stimuli → increases noradrenergic (NE) activity in CNS → NE stimulates glutamate release (excitatory NT) → promotes anxiety

What is the GABA receptor model of anxiety disorders?

GABA-A receptor system is impaired and/or downregulated → decreased/less CNS inhibition secondary to decreased GABA activity → uncontrolled anxiety

What is the serotonin 5-HT model of anxiety disorders?

5-HT is dysregulated → abnormal 5-HT activity in CNS → directly promotes anxiety OR indirectly promotes anxiety through dysregulation of NE neurotransmission

What are the uses of benzos?

anxiety, sleep, and seizures

List of benzos

What are non-benzos?

"Z-drugs" used for sleep

List of non-benzos

What is the MOA of benzos?

binds at a distinct site from the GABA binding site,

positive allosteric modulators of GABA-A,

increases CNS inhibitory effect of GABA at GABA-A

What happens when GABA is bound in benzos?

benzo binding induces an allosteric change in GABA-A → increases affinity of GABA for binding to GABA-A + increases frequency of Cl- channel opening

What happens when GABA is not present with benzos?

benzos do not impact Cl currents at GABA-A even if bound to GABA-A → binding of benzos shift the GABA concentration-response curve to the left

What is the MOA of barbiturates?

similar to benzos, BUT binds at a distinct site at GABA-A that is NOT the benzo binding site which increases DURATION that Cl- channel is open

What is the difference between Cl channels between benzos and barbiturates?

Benzos: increased frequency

Barbiturates: increased duration

True or False: barbiturates are not fatal upon overdose unless administered with other CNS depressants

False

Explanation: barbiturates ARE fatal upon overdose even when administered without other CNS depressants because of Cl- opening duration because they act as direct GABA agonists in place of GABA

What is the MOA of neuroactive steroids?

positive allosteric enhancement of GABA-A receptor that enhances GABA-A currents in a synergistic manner with diazepam

Explanation: different binding site than benzo binding site

What is the MOA of buspirone?

5-HT-1A receptor partial agonist that modulates 5-HT activity and may align with 5-HT dysregulation model of anxiety

Explanation: similar anti-anxiety effect of benzos, BUT does not have sedative, anticonvulsant, or habit-forming properties

What is the physiological effect of benzodiazepines?

increases the CNS inhibitory effect of GABA at GABA-A and allows Cl channels to open more FREQUENTLY

What is the physiological effect of barbiturates?

enhances the effects of GABA at GABA-A and allows Cl channels to open for a longer DURATION

What is the physiological effect of neuroactive steroids?

enhances GABA-A in a synergistic manner with benzos

What is the physiological effect of buspirone?

reduces anxiety similarly to benzos, BUT does not have sedating, anticonvulsant, or dependency properties

What are characteristics of benzodiazepine absorption?

nearly 100% oral absorption, but is also available for IM/IV administration

What are characteristics of benzo distribution?

lipophilic and extensive tissue distribution (including CNS)

What are characteristics of benzo metabolism?

extensively metabolized (has many steps)

- oxidative metabolism via CYP enzymes

- glucuronidation

What enzymes perform oxidative metabolism of benzos?

CYP3A4 and CYP2C19

Explanation: major isoforms catalyzing phase I metabolism of MOST benzos

Examples of benzos that do not undergo CYP450 metabolism

lorazepam, oxazepam, temazepam

LOTTTTTTT

True or False: all benzos under glucuronidation

True

Explanation: important phase II metabolism of all benzos

True or False: LOT benzos are indirectly glucuronidation

False

Explanation: they are directly

Which patient population is direct glucuronidation beneficial for?

those with liver insufficiency

True or False: many benzos have active metabolites that are converted from one benzo to another

True

Explanation: oxazepam is an active metabolite of diazepam

What are benzo drug interactions?

CYP3A4 induction,

CYP3A4 and CYP2C19 inhibition,

CNS depressants

How does CYP3A4 induction interact with benzos?

decreases dose if benzo

Examples: carbamazepine, phenytoin, phenobarbital, rifampin

How do CYP3A4 and CYP2C19 inhibitors interact with benzos?

increases dose of benzo

Examples: -azoles, CCBs, HIV protease inhibitors

How do CNS depressants interact with benzos?

increases CNS depression

Examples: alcohol, opioids

True or False: CYP3A4 interacts with neuroactive steroids

True

Example: zuranolone

What are drug interactions of buspirone?

CYP3A4 inhibitors/inducers and serotonergic agents

How do serotonergic agents interact with buspirone?

serotonin syndrome

What are adverse effects of benzos?

dependency,

drowsiness/sedation,

amnesia,

pregnancy

What are contraindications of benzos?

myasthenia graves,

hepatic impairment,

respiratory insufficiency

sleep apnea

True or False: overdose is rarely fatal when benzos are administered with other CNS depressants

False

Explanation: they are rarely fatal when benzos are administered alone, otherwise they have high risk of fatality due to profound CNS depression causing respiratory depression

What are adverse effects of neuroactive steroids?

FDA warning: excessive sedation and motor impairment

and CYP3A4 interaction

What are adverse effects of buspirone?

nausea, headache, jitteriness/akathisia

What are contraindications of buspirone?

monoamine oxidase inhibitor (MAOI) properties causes hypertensive crisis

Examples: MAOI antidepressants, linezolid, IV methylene blue

What is the MOA of flumazenil?

competitive antagonist at benzo receptors within GABA-A

Explanation: does NOT compete with GABA

What is the indication of flumazenil?

benzo reversal during procedure sedation, general anesthesia, or overdose

How is flumazenil administered?

IV

True or False: benzos shift a concentration-response curve to the right

False

Explanation: shifts it to the left and stays parallel

True or False: flumazenil shift a concentration-response curve to the right

True

Explanation: counteracts benzos