Nervous System- Anxiety By Schriefer

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Nervous System- Anxiety by Schriefer

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Nervous System- Anxiety by Schriefer

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Categories of Anti-Anxiety Agents

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Benzodiazepines
Buspirone
Miscellaneous (SSRI, et al)

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Benzodiazepines

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Chlordiazepoxide (Klor dye az e pox’ ide – Librium) – oldest
Diazepam (dye az’ e pam – Valium)
Oxazepam (ox az’ e pam – Serax)
Lorazepam (lor az’ e pam – Ativan)
Clorazepate (klor az’ e pate – Tranxene)
Prazepam (pray’ ze pam – Centrax)
Alprazolam (al pray’ zoe lam – Xanax)

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Dose response curve for barbiturates vs benzos, CNS depression.

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barbs have a linear relation. goes all the way up to coma and death.

benzos increase dose will stop at anesthesia.

benzos safer because you can't kill yourself as easily from CNS depression.

you get sedation that relieves anxiety without the significant drowsiness. benzos do this really well.

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benzo:
CNS – display a continuum of CNS depressant activity

where is the location of action?

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Selective antianxiety activity at a dose much lower than that for hypnotic activity

Hypnotic effect – suppresses REM sleep and stage 4 sleep

Locus of action: limbic system, brain stem reticular system. BZDs relieve anxiety by increasing inhibition in the limbic system, which is associated with control of emotional behavior. Hypnotic effect in RAS.

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what are some other pharm properties of benzos

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Some are anticonvulsants – act by ↓ spread of seizure activity at motor cortex.

Skeletal muscle relaxants – central action by increasing activation of GABA interneurons in the spinal cord. Used to treat spasms associated with various forms of motor neuron disorders.

Cardiovascular system – minor effect except in severe intoxication (one of the reasons why they're safer than barbiturates)

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Benzos MoA

which receptors?

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BDZ receptors in the CNS

Endogenous ligands of the BDZ receptors identified

BDZ-GABA-chloride ionophore (ligand –gated ion channel).
-Benzodiazepines facilitate the effect of GABA stimulation of GABA-A receptors leading to increased chloride permeability and increased inhibition.

chloride goes into the cell, cell becomes hyperpolarized, further away from the action potential, so it can't be activated or something.

benzo goes to its binding site, it increases the freq. of the opening of the chloride channel in response to GABA.

benzo's change the frequency! GABA needs to be present for benzos to work. think about a dimmer light switch.

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barbidurate

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barbitureates control the RATE.

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Benzodiazepine Pharmacokinetics

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All BDZ are equally efficacious as anxiolytics and sedative-hypnotics.
Pharmacokinetic properties determine the choice of drug under different clinical conditions.
Conversion to active or inactive metabolites is an important distinction. Most are extensively metabolized by CYP3A4 or CYP2C19.

*difference b/w drugs is in the pharmacokinetics

Lor-, Tem-, Oxazepam only are one step from glucuronide conjugate, so it's safer for liver. not converted to active metabolites.

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Benzodiazepines Adverse Effects

depends on what?

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Frequency of side effects increases with age, dose, duration of therapy, presence of liver disease and hypoalbuminemia

CNS:
-Drowsiness, ataxia, confusion, headache, euphoria, fatigue
-Paradoxical hyperexcitability,
-increased anxiety, insomnia

GI, hepatic, hematologic, menstrual disturbances, and disturbance of autonomic function – infrequent and mild

Fatal overdose. Incidence is low. More likely to occur when used in combination with other CNS depressants, e.g., alcohol and barbiturates

Teratogenic potential – safety to the fetus has not been proven (pregnancy category D)

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Benzodiazepines Tolerance, Dependence, and Withdrawal Reactions

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Tolerance may develop to CNS side effects and to anxiolytic, hypnotic effect upon CHRONIC use

Psychologic and physical dependence may develop upon high dose, chronic administration

Acute abstinence may precipitate withdrawal symptoms similar to barbiturate withdrawal reaction. Takes longer to develop and milder (not life threatening)
-Symptoms - Insomnia, agitation, recurrence of depression, exacerbation of psychosis, seizures

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Benzodiazepines:
Therapeutic Indications

ok so what else can benzos do?

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In addition to the treatment of anxiety, benzodiazepines are used in:
Treatment of alcohol withdrawal – diazepam, chlordiazepoxide, lorazepam
Insomnia
Preanesthetic medications – diazepam (before surgery)
Neuromuscular disorders
Anticonvulsant
Premenstrual dysphoric disorder

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Benzodiazepines:
Potential Drug-Drug Interactions

what's the important one to remember?

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*CNS depressants including alcohol – enhancement
Smoking – decrease effect
Caffeine – decrease effect
Benzodiazepine antagonists – flumazenil (Mazicon)
SSRIs, GRAPEFRUIT juice inhibit CYP3A4 and increase BZD levels

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Buspirone. how does it work? How is it different from other BDZs in terms of onset of activity? In what ways is it better/worse than BDZs.

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Buspirone (byoo spye’ rone – Buspar) is a non-benzodiazepine anxiolytic. It appears to reduce anxiety by acting as a partial 5HT1A agonist.

It also differs from the benzodiazepines in that there is a delayed onset of activity, less sedation, no anticonvulsant activity, no muscle relaxation, and NO potential for abuse. It does not potentiate CNS depressants such as alcohol.

Anxiety related traits are associated with altered serotonin transporters, so perhaps buspirone represents a more specific therapy for anxiety.

adverse: generally well tolerated, but Tachycardia, palpitations, nervousness, GI distress, and paresthesias

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Clomipramine

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A tricyclic used in the treatment of obsessive-compulsive disorder (OCD). 5HT reuptake blocker. Fluvoxamine and alprozolam also used

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Miscellaneous Agents

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Don't use these unless you have to:
Barbiturates
Meprobamate
Antihistamines

Antipsychotics and Antidepressants (starting to become first line)
Beta blockers (performance anxiety, slow down heart rate)

Kava – an herbal remedy possibly effective in relieving anxiety. However, recent evidence of hepatoxicity means patients should be warned to avoid Kava.

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Types of anxiety and the drug treatment:

situational:
anxiety in response to illness:
generalized anxiety disorder:
social phobia:
Performance anxiety:
Panic Disorder:
OCD:
post-traumatic stress disorder:

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Situational anxiety – does not usually require drug treatment
Anxiety in response to illness – benzodiazepines (acute anxiety), ssri (chronic anxiety)
Generalized anxiety disorder –SSRI, buspirone, benzodiazepines
Social phobia – cognitive behavioral therapy, SSRI, clonazepamPerformance anxiety – beta-blockers
Panic Disorder – SSRI, clonazepam
Obsessive-Compulsive Disorder – clomipramine, SSRI
Post-traumatic stress disorder – cognitive behavioral therapy, SSRI

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Muscle Relaxing Drugs (Spasmolytics)

Spasticity – an increase in tonic stretch reflexes and flexor muscle spasms, and muscle weakness.
Associated with stroke, MS, CP or spinal injury.

Goal of tx: Goal is to decrease activity of Ia neurons activating primary motor neurons or to increase activity of inhibitory internuncial neurons.

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ok thanks.

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Diazepam

where does it work? how high of a dose?

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Diazepam
Action as a spasmolytic due to increased GABAA-mediated Cl -1 conductance in motor neurons.
Higher doses than those needed to relieve anxiety

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Baclofen (Lioresal)

where does it work on?
ass'd with what type of channels?
results in relaxation of muscle from what?

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Baclofen (Lioresal)
An agonist at GABAB receptors;
its action results in increased K+ conductance and hyperpolarization of neurons.
This results in inhibition of glutamate neurons in brain and spinal cord, and , thus, relaxation of muscles.

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Baclofen. how can you take it? what are adverse effects?

what ISN'T there (which is a good thing)?

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Oral or intrathecal administration
Adverse reactions:
Drowsiness
Seizures in pts with epilepsy
NO decrease in muscle strength (yes for diazepam)

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Tizanidine (Zanaflex)

how does it work?

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An α2-adrenergic agonist (similar to clonidine);
Potentiates pre- and post-synaptic inhibition in spinal cord.
*increasing inhibition!

Adverse reactions (generally well tolerated)
Drowsiness
Dry mouth
Hypotension
Weakness (but not baclofen)

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Dantrolene (Dantrium)

which receptor?
what else is it used for?

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Blocks the rayanodine receptor channel, which, in turn, interferes with excitation-contraction coupling in skeletal muscle.

Adverse reactions
Generalized muscle weakness
Sedation

Also used to treat malignant hyperthermia, a genetic disorder in which there is an inability to sequester calcium. Hyperthermia is triggered by anesthetics or succinylcholine.

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Treatment of Local Muscle Spasms

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Carisoprodol (Soma; not SOMA)
Chlorphenesin
Chlorzoxazone (Paraflex)
**Cyclobenzaprine (Flexaril)--> know this one, if at all.
Metaxalone (Skelexin)
Methocarbamol (Robaxin)
Orphenadrine (Norflex)

Act in spinal cord to inhibit muscle stretch reflex. kinda unsure.