Benzodiazepines

What happens when there is too much glutamate?

sweating, anxiety, migraines, tics etc

What is the principle precursor for GABA

glucose

What are the basic steps for the glucose to GABA pathway

glucose

TCA cycle

a-ketoglutarate

GABA shunt

GABA-T

Glutamate --> GABA

via glutamate decarboxylase

needs vitamin B6

GABA to the citric acid cycle

needs to become succinate semialdehyde first

Succinate semialdehyde to the citric acid cycle, becomes glutamate via

glutamate synthase

glutamate --> glutamine

glutamine synthetase

What is the primary inhibitory neurotransmitter of the CNS

GABA

what does GABA release do (basics)

increases Cl in the postsynaptic neuron and causes hyperpolarization

no action potential

Describe the makeup of the GABA A receptor

heteropentamer composed of two alpha subunits and two beta subunits

with a central Cl ion channel that is ligand gated

True or False, the GABA A receptor is ligand gated

True

where do BZDs bind on the GABA A receptor

the gamma (y)

True or False, BZDs, barbiturates and GABA all bind at different sites on the GABA A receptor

True

Applications for BZDs

anxiety

epilepsy

insomnia

spasticity

anesthetize

alcohol detoxification

True or False, BZDs are used due to the selectivity and high margin of safety

True

How do BZDs act on the GABA A receptor and what do they promote

increase the frequency of the Cl channel opening and increases GABA binding

What is true about BZDs:

1. dose dependent CNS depression

2. Long acting are not used as anxiolytics for long term use

3. Work quickly

4. Work slowly taking weeks to months to have significant effects

1,3

which drug (BZD) causes anterograde amnesia

midazolam

True or False, Xanax is a BZD that is short acting

true, xanax is aka alprazolam

What kind of BZD is valium

a long acting BZD

What do you need to ensure the patient does before coming to the appointment if they are going to be taking BZDs

ensure they have a ride home they cannot drive!

Effects of BZDs on the CNS

dose dependent depression

drowsiness, sedation

certain drugs will produce anterograde amnesia

muscle relaxation

antiseizure

Effects of BZDs on the heart

normal dose has minimal effect

greater doses decrease BP, cardiac output, and stroke volume

Effects of BZDs on the lungs

respiratory depression

ventilatory assistance reported being needed in some neonates

clinically significant respiratory depression can occur if opioid used in combination with midazolam

True or False, opioid use is a contraindication of midazolam

True

what is the onset of lipid soluble drugs compared to water soluble drugs

faster onset for lipid than water

what is the elimination rate of lipid soluble drugs and why is that?

the lipophilic properties allow it to be stored in adipose tissue and this slows the elimination rate

Which type of patient has a reduced ability to metabolize BZDs (especially longer acting ones)

elderly pts

What are the side effects of BZD use in elderly patients

dementing (confusion)

depression

loss of coordination --> fall risk

Diazepam contains propylene glycol and ethyl alcohol solvents that are associated with local pain, phlebitis and thrombosis when injected via hand or wrist, what can you combat this with

water soluble midazolam

Why are BZDs contraindicated for patients with narrow angle glaucoma

because they affect pupillary muscles

What is true about BZDs and pregnancy:

1. BZDs can cross the BBB

2. Triazolam is category X

3. Large doses during delivery may result in respiratory depression of the neonate

4. First trimester short term use can be associated with fetal malformations

1,2,3

4 is for long term use not short term

BZD drug interaction with alcohol

combining sedatives creates a summative effect and risk of overdose

Rifampin with BZD use

Rifampin is an antibiotic typically used in TB that increases the metabolism of BZDs and this warrants the use of alternative anxiolytic agents as it reduces its bioavailability

BZD and carbamazepine

an anticonvulsant that can induce hepatic enzymes for metabolism of BZDs and greatly reduce sedative effects and may lead to loss of seizure control

Calcium channel blockers and BZDs

inhibit CYP enzymes, peak the concentrations by 2-3X and increase sedation avoid in elderly!

BZDs with Erthromycin and clarithromycin (antibiotics) Ketoconazole and itraconazole (antifungals) Indinavir, nelfinavir, ritonavir (antivirals)

Decreased first-pass metabolism and improving bioavailability - blood concentrations of BZs increase. May lead to over-sedation and respiratory depression. Best BZs for liver-impaired patients: oxazepam & lorazepam

Grapefruit Juice and BZDs

juice can increase blood concentrations of BZDs

what is the only FDA approved BZD receptor antagonist

Flumazenil

Flumazenil effect

Can usually reverse a benzodiazepine-induced overdose in 1-2 minutes

Z drugs compared to BZDs

Produces sedation but less memory and cognitive impairment than BZs, and little skeletal muscle relaxation or anticonvulsant activity.

Are Z drugs contraindicated in narrow angle glaucoma patients like BZDs are?

No

Function of MT1 and MT2 melatonin receptors

promote sleep, regulate reproduction and immunity, and inhibit aging and cancer growth.

Insomnia drugs

Agomelatine and ramelteon

True or False, Ramelteon has no affinity for GABA receptor, and no anterograde amnesia

True

What complicates the use of barbiturates in anesthesia

increases respiratory reflex activity which complicates its use in anesthesia

How do Barbiturates affect the CNS

dose dependent

diminished response and performance

decrease time spent in REM

How do Barbiturates at high doses affect the heart

decrease BP, cardiac output and stroke volume

True or False, Barbiturates have been mostly replaced by BZDs

True

What is the mechanism of barbiturate action

increases the duration of Cl- channel opening in the GABA-A receptor

Can barbiturates be used in patients with porphyria

No

absolute contraindication

they introduce P450 enzymes which contain heme

Chloral Hydrate and nitrous oxide

may depress the CNS in children to such an extent that the child protective reflexes become compromised (choking, aspirating)

True or False, Chloral hydrate can be detected in the breast milk but peak concentrations are not enough to sedate the infant.

False, it is enough

What is the caution about Chloral hydrate

is a mutagen and can cause chromosomal damage. It is also a metabolite of trichloroethylene, an industrial solvent, environmental contaminate, and carcinogen

Antihistamines effect on the CNS

Mild CNS depression

anticholinergic, antihistaminic

analgesic

drowsiness and dry mouth

Antihistamine effect on heart

antiarrhythmic properties

Antihistamine effect on lungs

bronchodilation

How is Buspirone a unique anti anxiety drug

A partial 5-HT1A agonist at pre and postsynaptic receptors Therapeutically equivalent to diazepam, but lacks the more prominent CNS depression and the anticonvulsant/muscle relaxant properties of the BZs. Can take with alcohol - major advantage over BZs

Why is buspirone use limited in dentistry

because it have a 1-3 week clinical effect time restriction

Centrally acting muscle relaxants vs peripherally acting muscle relaxants

Centrally acting muscle relaxants work within the central nervous system, like the brain and spinal cord, to reduce muscle tension and spasms, while peripherally acting muscle relaxants directly affect muscle fibers, typically at the neuromuscular junction. Centrally acting relaxants are often used to treat spasticity and muscle spasms associated with conditions like cerebral palsy or stroke, while peripherally acting relaxants are mainly used for muscle relaxation during surgery and anesthesia.

True or false: Centrally acting muscle relaxants cause voluntary muscles to relax by CNS depression

True

What is the example of a centrally acting muscle relaxant, orphenadrine used for

patients with Parkinson's

What can be used for TMD short term

CNS muscle relaxant cyclobenzaprine

Why should caution be taken when prescribing CNS muscle relaxants to pts taking anticoagulants

induction of drug and hormone metabolizing liver enzymes

Why should patients taking diazepam avoid xanthine contain foods like coffee, cocoa, and coke

partially reverses the muscle relaxant actions of diazepam

True or False, propranolol is approved for the treatment of anxiety

False, it is effective in decreasing the peripheral autonomic symptoms like tremors and tachcardia but NOT anxiety

True or False, Dexmedetomidine lacks respiratory depression effects

True

Uses of clonidine

nasal decongestant with reduction in BP (sudden withdrawal leads to rebound hypertension 20 hours after cessation) -oral premedicant in patients with pretreatment anxiety. -useful in the treatment of opiate, cocaine, food, and tobacco withdrawal