Neuroscience Week 3: Benzos and Barbs Flashcards
Describe the differences between barbiturates and benzodiazepines in pharmacokinetic and pharmacodymanic factors
Describe the neuronal mechanism of actions of the anxiolytic (sedative) drugs.
Understand the main side effects, drug interactions, toxicities, issues of tolerance of the sedative drugs.
How do spasmolytic drugs act and where do they act?
Understand the key side effects with the skeletal muscle relaxants (spasmolytic agents)
Katzung Basic & Clinical Pharmacology Chpt 22 and 27
Ideal Sedative characteristics
Anxiolytic - calming
little effect on motor or mental function
little CNS depression
often will produce hypnosis with a high enough dose
Ideal Hypnotic Characteristics
- produce drowsiness encourage sleep (onset and maintenance)
- more pronounced CNS depression
Clinical Uses of Sedative-hypnotics
- For the relief of anxiety
- For insomnia
- For sedation and amnesia before and during medical and surgical procedures
- As a component of balanced anesthesia (intravenous administration)
- For treatment of epilepsy and seizure states
- For control of ethanol or other sedative-hypnotic withdrawal states
- For muscle relaxation in specific neuromuscular disorders
- Treatment of serotonin syndrome (benzodiazepines along with blocking serotonin synthesis with cyproheptadine )
Treatment of serotonin syndrome
(benzodiazepines along with blocking serotonin synthesis with cyproheptadine )
Barbiturate Examples
4 listed
- Phenobarbital
- Pentobarbital
- Secobarbital
- Thiopental
Benzodiazepines Examples
- Alprazolam
- Chlordiazepoxide
- Diazepam
- Midazolam
- Lorazepam
- Oxazepam
- Flumazenil (antagonist)
Nonbenzodiazepines hypnotics Examples
3 listed
- Zolpidem
- Zaleplone
- Eszopiclone
5-HT-1A agonist anxiolytic examples
Buspirone
Benzodiazepines and Barbiturates examples
- Benzodiazepines bind to receptors
- Barbiturates bind inside the Cl- channel so it is difficult to reverse this
Barbiturates MOA features
- ↑duration of channel opening
- nonspecific membrane actions
- no specific antagonist
- overdose risk
Benzodiazepine MOA features
↑ frequency of channel opening
acts predominately at the GABAA receptor
antagonist = flumazenil (RO15- 1788)
Antagonist of Benzodiazepines
Flumazenil
Factors that affect Barbiturate duration of action
- •Lipid solubility The higher the ↑ lipid solubility the ↑redistribution rate and the ↑ cyto P450 metabolism
- protein binding
- extent of ionization (pka)
Barbiturates Pharmicokinetic tolerance
Increasing capacity to metabolize barbiturates overtime due to the induction of cytochrome P450 enzymes
Barbiturate Pharmacodynamic tolerance
Increasing amounts of barbiturate at the target site will be required to maintain a given level of drug action on the target site.
Barbiturate Toxicity
- Maintain airways, supportive measures hydration, forced diuresis and alkalization, often not enough and hemodialysis is needed
- only the unionized form is reabsorbed therefore ionize the blood and urine by ↑ pH (Sodium bicarbonate)
- Inducing emesis only if drug was very recently taken and there are no signs. Activated charcoal modestly effective if given soon after the drug is taken. CNS stimulants like Bemegride can be given. There is No direct reversal agent Respiratory arrest occurs at 4X lower dose and cardiac arrest
Advantage of Benzodiazepines
- higher therapeutic index
- lower incidence of tolerance
- lower abuse liability
- fewer drug interactions and side effects
Factors responsible for benzodiazepine onset and duration of action
- ↑ Lipid solubility- decreases onset time and increases protein binding and redistribution
- Generation of active metabolites (critical for the duration of action) ↑ duration of action
- metabolized through microsomal enzymes but not inductive.
- Renal excretion
Important consideration for Benzodiazepines: Lorazepam example
5 different active metabolites
Factors affecting Biodisposition of Benzodiazepines
- Elderly patients and those with liver dysfunction will have longer elimination half-lives of most benzodiazepines and all barbiturates. Need to reduce the dose. Will see more sedation and more amnesia in the elderly.
- Metabolism involving glucuronide conjugation is less affected by old age or liver disease than oxidative metabolism
- Lorazepam, Oxazepam and Temazepam are conjugated extrahepatically (glucoronidated). Can be used in the presence of liver dysfunction
Benzodiazepines that can be used in elderly and those with liver disfunction
Lorazepam, Oxazepam and Temazepam are conjugated extrahepatically. Can be used in the presence of liver dysfunction
Are benzodiazepines really a wonder drug?
- Pharmacodynamic tolerance occurs particularly with long acting benzos
- Abuse does occur, albeit infrequently, typically with the short acting benzos
- Cross-tolerance and overdose can occur with other sedative-hypnotics
- Withdrawal syndrome can occur and removal is best done gradually.
- Flumazenil is a benzodiazepine antagonist and is used to reverse CNS effects of bdzs and some of the newer ‘non-bdzs’ (zolpidem, zalephon, eszopiclone)
‘non-bdzs’
(zolpidem, zalephon, eszopiclone)
Serotonin Syndrome and treatment with Benzodiazepines
- Excess synaptic serotonin can lead to a potentially fatal syndrome. Clinical presentation is hypertension hyperreflexia, tremor, clonus, hyperthermia, hyperactive bowel sounds, diarrhea, mydriasis, agitation coma. Onset occurs within hours. Brought on by SSRIs, second-generation antidepressants MAOIs, sumatriptan MDMA, tramadol, fentanyl.
- Treatment is benzodiazepines and supportive measures
Benzodiazepines and barbiturates sleep architecture
problematic for chronic users ↓ REM sleep and ↑ REM latency
Zolpidem
Ambien®, Zaleplon Sonata®, Eszopiclone Lunesta ® :short-acting, fewer amnesic effects, does not negatively affect sleep architecture, increases Slow wave sleep, metabolized by CYP 3A4, additive with ethanol. Acts at the Benzodiazepine site to increase GABA-A activity.
Buspirone
BuSpar® partial agonist at 5-HT1A for generalized anxiety, no additive effect with sedative hypnotics. Reduces and delays onset of REM sleep. Tolerance development is minimal, little or no rebound anxiety or withdrawal. Metabolized by CYP3A4 Can cause tachycardia + paresthesias
Meprobamate
Equanil®, Miltown® | Trancot™ unknown, anxiolytic
Chloral Hydrate Aquachloral®
Chloralum™ trichloroethanol, for sedativehypnotic adjunct to analgesics, interacts with other sedative hypnotics. Has minor effects on REM.
Spasmolytics-Skeletal Muscle Relaxants: Direct acting agents
- Dantrolene (Ryanodex)
- Anobotulinum toxin type a (BoTox)
- Abobotulinum toxin type a (Dysport)
Spasmolytics-Skeletal Muscle Relaxants: Centrally acting agents
- Diazepam (Valium)
- Baclofen (Lioresal)
- Cyclobenzaprine (Flexeril)
- Riluzole (Rilutek)
- Tizanidine (Zanaflex)
Reflex arc and inhibitory arc
Dantrolene MOA
works at the internal sarcoplasmic ryanodine (RYR) Ca2+ channels to inhibit them
Dantrolene Function
- Decreases muscle contraction by directly interfering with calcium ion release from the sarcoplasmic reticulum within skeletal muscle cells.
- This “uncouples” the excitation-contraction process,
- useful in treating malignant hyperthermia, a rare autosomal dominant disease precipitated by the use of neuromuscular blocking agents
Malignant Hypothermia is treated with?
Dantrolene
Botulinum Toxin mechanism of action
- produced by C. botulinium
- Proteolytic cleavage of the SNARE Complex involved in neurotransmitter release
Botulinum Toxins- Serotype A onabotulinumtoxinA (Botox), abobotulinumtoxinA (Dysport), and incobotulinumtoxinA (Xeomin); serotype B is rimabotulinumtoxinB (Myobloc).
Botulinum toxin is a neurotoxic protein produced by Clostridium botulinum and related species. Cleaves SNARE complex proteins (SNAP-25, synaptobrevin, syntaxin) required for ACh vesicle fusion at neuromuscular junction.
Botulinum Toxins procedure
- Serotypes A and B are administered for spasticity management. The response is generally dose-dependent; thus, the more toxin is injected, the greater is the resulting muscle weakness.
- The effects occur within 24–72 hours after injection. The peak effect occurs at approximately 4–6 weeks and has a duration of 2–6 months. This 2- to 6-month duration is the timeframe for collateral sprouting of the axon.
Botulinum Toxins Side effects and complications
The side effects and complications: weakness, pain at the injection site, infection, flu-like syndrome, dysphagia with cervical injections, nerve injury, respiratory failure, and antibody formation.
Baclofen MOA
- GABA-B agonist used to treat spasticity, improve mobility in patients with multiple sclerosis and other spinal cord lesions
- works mainly at the level of the spinal cord to block polysynaptic afferent pathways and, to a lesser extent, monosynaptic afferent pathways.
- acts as an inhibitory neurotransmitter itself or by hyperpolarizing the primary afferent nerve terminals, which inhibits the release of excitatory neurotransmitters such as glutamate and aspartic acids.
- drug works at supraspinal sites as well
Cyclobenzaprine AKA
Flexoral
Cyclobenzaprine MOA
- Similar to amitriptyline in chemical structure, some of its effects are similar to the tricyclic antidepressants, including anticholinergic activity, potentiation of norepinephrine, and antagonism of reserpine.
- Cyclobenzaprine relieves muscle spasms through a central action, possibly at the brain stem level
- No direct action on the neuromuscular junction or the muscle
- similar to the action of TCAs
Cyclobenzaprine similar agents
Other similar agents: carisoprodol, chlorphenesin, metaxalone, methocarbamol, orphenadrine
Cyclobenzaprine adverse effects
Causes a great deal of sedation, confusion and can cause visual hallucinations due to antimuscarinic effects
Tizanidine MOA
a central-acting alpha2-adrenergic agonist acts presynaptically and postsynaptic within the cord
structurally and pharmacologically related to clonidine
decreases the release of excitatory amino acids which in turn leads to inhibition of spinal motor neurons
Tizanidine Adverse Effects
- produces more drowsiness and sedation than baclofen
- not associated with the muscle weakness which may occur with baclofen therapy
- Given this is an alpha 2 agonist it ↑ BP
- Dry mouth
Riluzole and Idrocilamide MOA
Benzothiazole- inhibits glutamate transmission and improves energy metabolism in muscles.
Riluzole inhibits the release of glutamate by interfering with sodium (Na+) channels required for glutamate release
For the treatment of amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). Reduces spasms.
Riluzole and Idrocilamide in Huntingtons and ALS
For the treatment of amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). Reduces spasms
The altered huntington protein in people with HD is believed to interfere with aerobic respiration, cells must resort to anaerobic respiration, eventually leading to cell death.
Riluzole special considerations
- Riluzole extends survival and/or time to tracheostomy.
Riluzole and Idrocilamide Adverse effects
- Side effects: asthenia, decreased lung function, pneumonia, vertigo, paresthesia, anorexia, and somnolence.
Other Centrally Acting Spasmolytic Drugs
Riluzole and Idrocilamide Overview
Tizanidine Overview
Cyclobenzaprine Overview
Baclofen Overview
Identify
A. α2 R - tizanidine
B. GABAB - Baclofen
C. GABAA Benzodiazepines
D. Muscle - Dantrolen or Botox
WHAT IS THE PRIMARY GOAL OF A HYPNOTIC DRUG?
A. To calm the patient and reduce anxiety
B. To encourage sleep
C. To induce a state of suggestibility
B. To encourage sleep
IF YOU WANTED TO DESIGN A DRUG TO HELP REDUCE ANXIETY AND ENCOURAGE SLEEP THAT DRUG WOULD LIKELY PRODUCE WHAT EFFECT? A. Increase glutamate activity
B. Increase norepinephrine activity
C. Increase GABA activity
C. Increase GABA Activity
A PERSON TAKING BARBITURATES TO MANAGE SEIZURES WILL NEED A HIGHER THAN NORMAL CONCENTRATION OF A BENZODIAZEPINE TO PRODUCE SEDATION AND TO DECREASE ANXIETY. WHY?
Target the same receptor
both increase chloride conduction and hyperpolarize the cell to make it less likely to fire
Crossover of tolerance (maybe uncouple, change receptors, etc.)
Target if you want to encourage sleep
Agents for Sleep
- Benzodiazepines and barbiturates
- Non-benzodiazepines: Zolpidem Ambien®, Zaleplon Sonata®, Eszopiclone Lunesta ® :short-acting, fewer amnesic effects, does not negatively affect sleep architecture, increases Slow wave sleep, metabolized by CYP 3A4, additive with ethanol
- Buspirone BuSpar® partial agonist at 5-HT1A for generalized anxiety, no additive effect with sedative-hypnotics. Reduces and delays onset of REM sleep. Tolerance development is minimal, little or no rebound anxiety or withdrawal. Metabolized by CYP3A4 Can cause tachycardia + paresthesias
- Meprobamate Equanil®, Miltown® | Trancot™ unknown, anxiolytic
- Chloral Hydrate Aquachloral® | Chloralum™ trichloroethanol, for sedative-hypnotic adjunct to analgesics, interacts with other sedative hypnotics. Has minor effects on REM.
- Ramelteon Rozerem®, Tasimelteon MT receptor agonist, rapid sleep onset, active metabolite from CYP1A2, does not alter sleep architecture
- Suvorexant- orexin antagonist.
Which drug?
- Barbiturate has actions other than GABA at reasonable doses
- Benzodiazepine doesn’t act unless GABA is present
Which drug will have a faster onset of action ? Barbital or Thiopental?
For Barbiturates, as lipid solubility decreases, the delay in onset of action increases, protein binding decreases, and renal excretion increases.
Thiopental is more lipid soluble than Barbital.
the more water soluble a drug the more likely to pee it out
Thiopental is faster
WHICH FORM OF THE DRUG IS ABSORBED?
A.Ionized B. Unionized
B. Unionized
IF YOU KNOW THAT BARBITURATES ARE WEAK ACIDS AND PHENOBARBITAL PKA IS 7.3 PENTOBARBITAL PKA IS 8.0 WHICH WILL BE MORE IONIZED BY ALKALINE CONDITIONS?
A. Phenobarbital
B. Pentobarbital
C. Both will be equally ionized in alkaline urine
A. Phenobarbital
because it is further away from the pH making it more ionized
MARILYN MONROE WAS PRESCRIBED BARBITURATES FOR SLEEP AND IT WAS FOUND THAT SHE WAS HAVING TO INCREASE HER DOSE JUST TO GET TO SLEEP. MARILYN MONROE DIED OF AN OVERDOSE OF BARBITURATES, BUT WHAT WAS THE LIKELY CAUSE OF HER TOLERANCE TO THE THERAPEUTIC EFFECT OF BARBITURATES AND HOW COULD IT CONTRIBUTE TO HER DEATH?
why was she tolerant to the sleep effect but not respiratory depression and death?
- Give Sodium Bicarb to alkalize the urine to drive the drug out
- tolerance to the therapeutic effects but not the lethal effects
- OVERDOSE RISK Tolerance develops to the therapeutic actions of barbiturates, thus increasing the ED50 but not to the lethal effects so the LD50 does not increase. Overtime the therapeutic safety margin??? declines.
Barbiturate OD Treatment
Give Sodium Bicarb to alkalize the urine to drive the drug out, dialysis, hemodialysis
A PATIENT COMES INTO THE ER WHO HAS TAKEN AN OVERDOSE OF PENTOBARBITAL OVER AN HOUR AGO. AFTER SUPPORTING HIS BREATHING, WHICH COURSE OF ACTION IS MOST LIKELY TO HELP ACCELERATE REMOVAL OF THE DRUG FROM HIS SYSTEM?
A.Administration of a cytochrome p450 inhibitor
B.Administration of activated charcoal
C.Administration of naloxone.
D.Administration of NaHCO3
E.Administration of intravenous diazepam
D. Administration of NaHCO3
Sodium Bicarbonate to alkalize the urine to keep more of the drug ionized
BENZODIAZEPINES ARE CONSIDERED TO BE A SAFER DRUG THAN BARBITURATES. WHAT MAKES THEM SAFER THAN BARBITURATES? WHAT IS THE MECHANISM FOR THIS HIGHER SAFETY MARGIN? WHAT IS DIFFERENT ABOUT BENZODIAZEPAM RELATIVE TO BARBITURATES
the difference between the effective dose and lethal dose
A PATIENT WHO HAS USED BENZODIAZEPINES CHRONICALLY TO TREAT GENERALIZED ANXIETY DECIDES THAT SHE CANNOT AFFORD HER MEDICATION AND ABRUPTLY STOPS. SHE IS LATER ADMITTED TO THE HOSPITAL BECAUSE OF ELEVATED ANXIETY AND SEIZURES. WHAT IS THE REASON FOR THIS?
Due to tolerance the brain is producing less GABA or GABA Rec or increase things that GABA works against, increase glutamate or activity or whatever she’s having an adjustment, so will see the opposite of what the drug does
Benzos and Barbs MOA
BEnzos increase the frequency of opening
Barbs increase duration of opening
A PATIENT HAS ANXIETY WHEN FLYING. SHE IS PLANNING ON TAKING A SHORT AIRPLANE FLIGHT. THE BEST CHOICE FOR SEDATION WOULD BE ALPRAZOLAM, WHY?
A. Because it is less likely cause gastric irritation
B. Because it does not generate active metabolites
C. Because it will not interact with other sedatives like alcohol.
D. Because it has a high degree of lipid solubility and will act quickly.
B.
- ATOM - Alprazolam, Triazolam, Oxaepam, Midazolam-short acting BDZs
- LOT - Lorazepam, Oxazepam Temazepam-only undergo glucoronidation extrahepatic
ATOM for
Short acting BZDs
LOT for
elderly or hepatic deficient patients
MEtabolism of Lorazepam
AN 82-YEAR-OLD WOMAN, OTHERWISE HEALTHY FOR HER AGE, HAS DIFFICULTY SLEEPING. DIAZEPAM IS PRESCRIBED FOR HER AT ONE HALF OF THE CONVENTIONAL ADULT DOSE. WHICH STATEMENT ABOUT THE USE OF DIAZEPAM IN THIS ELDERLY PATIENT IS ACCURATE?
(A) Ambulatory dysfunction is unlikely to occur in elderly patients taking one half of the conventional adult dose
(B) Hypertension is a common adverse effect of benzodiazepines in elderly patients
(C) Over-the-counter cold medications may antagonize the hypnotic effects of the drug
(D) The patient may experience amnesia, especially if she also consumes alcoholic beverages
(E) Diazepam does not cause rebound insomnia on abrupt discontinuance
D. The patient may experience amnesia, especially if she also consumes alcoholic beverages
THE MOST LIKELY EXPLANATION FOR THE INCREASED SENSITIVITY OF ELDERLY PATIENTS AFTER A SINGLE DOSE OF A BENZODIAZEPINE IS
(A) Age-dependent changes in brain function
(B) Decreases in plasma protein binding
(C) Decreased metabolism of lipid-soluble drugs
(D) Decreases in renal function
(E) Increased cerebral blood flow
(A) Age-dependent changes in brain function
A 40-YEAR-OLD PATIENT WITH LIVER FAILURE COMES IN FOR A SURGICAL PROCEDURE. WHICH OF THE FOLLOWING PREANESTHETIC SEDATION MEDICATIONS CAN BE SAFELY USED WITHOUT CAUSING EXCESSIVE CNS DEPRESSION?
A. Diazepam
B. Pentobarbital
C. Lorazepam
D. Chloradiazepoxide
E. Phenobarbital
Lorazepam
DANTROLENE ACTS AS A SPASMOLYTIC BY
A . Directly decreases excitability of the motor neuron in the reflex arc.
B. Acting within the spinal cord to decrease muscle spasticity.
C. Inhibiting acetylcholine receptors at the neuromuscular junction.
D. Decreasing calcium release from the skeletal muscle sarcoplasmic reticulum.
E. Activating GABAA / benzodiazepine receptors in the CNS.
D. Decreasing calcium release from the skeletal muscle sarcoplasmic reticulum.
