Which class of drug is more clinically useful: GABA agonists or antagonists?

 NMDA agonists or antagonists? Why?

GABA receptors are the major inhibitory neurotransmitter in the CNS. Therefore when you stimulate them, they cause sedation and anxiolysis by allowing Chloride (anion) into the cells causing hyperpolarization.

GABA agonists are more useful clinically for sedation, to provide anxiolysis, and some drugs even have anticonvulsant activity. (Ex. Benzodiazepines, barbiturates)

GABA antagonist are not clinically useful. They are used in the lab to mimic seizures for research.

NMDA-glutamine receptor stimulation in the CNS appears to be critical for the formation of certain memories; however, overstimulation of these receptors has an excitotoxic effect (by allowing too much Na and Ca ions to enter the neuron) and is suggested to be a mechanism for neurodegenerative or apoptopic processes.

NMDA receptor antagonists are more important clinically because they are considered to be neuroprotective. They block the NMDA receptors which prevents overstimulation. Ex. Memantine (used for Alzheimer’s disease), Riluzole (ALS treatment), Ketamine (anesthetic), Nitrous oxide, PCP, Methadone, Tramadol, among many others.

NMDA agonists are not clinically useful. They are mainly used in research.

The mechanism of action of Benzodiazepines is that of a GABA agonist. They cause their effects binding to a specific high-affinity site located at the interface of the alpha and gamma-2 subunit on the GABA receptor. This binding to GABA leads to an increase in chloride (anion) conductance, which causes hyperpolarization of the cell and therefore, a decrease in excitability.

Therapeutic uses include:
Anxiety disorders: (panic disorder, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, anxiety/depression of schizophrenia, and extreme anxieties with specific phobias.)

Muscular disorders: skeletal muscle spasms, such as occur in a muscle strain (diazepam), and treating spasticity from degenerative disorders, such as in multiple sclerosis and cerebral palsy.

Amnesia: premedication for procedures and also for use during conscious sedation.

Seizures: Epilepsy maintenance treatment (clonazepam), diazepam and lorazepam are the drugs of choice for terminating grand mal epileptic seizures and status epilepticus. Also useful in preventing alcohol withdrawal seizures.

Sleep disorders: flurazepam (Dalmane), temazepam (Restoril), and triazolam(Trilam). (Not the preferred drugs.)

Briefly outline the pharmacology of flumazenil?

 How does flumazenil compare to physostigmine?

Flumazenil (Romazicon) is a GABA-receptor antagonist. It causes reversal of the benzodiazepines effect by competitive inhibition at the GABA receptor. Therefore, it is used as an antidote and reversal drug. It is only available as an IV drug with a rapid effect and short half-life. 

Flumazenil may precipitate an acute abstinence (withdrawal) reaction in patients addicted to benzodiazepines, and, it may also induce seizures. Because it has a short duration of action, repetitive dosing may be required when administered for reversal of long-acting benzodiazepines.

Physostigmine (Antilirium) is an indirect acting cholinergic agonist. It causes these effects by inhibiting acetylcholinesterase. It is a tertiary amine so it can cross the blood brain barrier with ease. Physostigmine may be used to antagonize the delirium and CNS depressant effects of benzodiazepines; therefore, it could be useful to manage undesired effect of benzodiazepines. Little is known about how these actions occur but studies suggests that it may cause an additive effect of the two neurotransmitter systems rather than a direct interaction at the central receptor sites. Physostigmine should not be used in the instance of a benzodiazepine overdose because of it is nonspecific and has a potential toxicity. Flumazenil is the drug of choice for benzodiazepine reversal.

Note: If you administer physostigmine to patients confused or comatose from high doses of benzodiazepines or anticholinergics (this includes TCAs, atropine and scopolamine), the confusion will improve and often they will wake up from a drug-induced coma (this is where the name Antilirium comes from). It makes sense that physostigmine will counteract CNS side-effects of anticholinergics. What is not intuitive, but interesting, is that if you increase ACh levels with physostigmine, you can also counteract symptoms of benzodiazepines (which do not work on ACh receptors) and that increasing CNS ACh levels helps patients with Alzheimer's Disease.

 What is GHB?

 Name two receptor classes that may mediate the actions of GHB.

GHB (gamma-hydroxybutyrate) is a naturally occuring substance found within the body. Used as a general anesthetic as well as to treat insomnia, clinical depression, narcolepsy, and alcoholism. It is also used as an intoxicant and is otherwise known as "the date rape drug"

GHB is an agonist at the GHB receptor, which is excitatory and it is a weak agonist at the GABA-B receptor, which is inhibitory.

Why is the half-life of midazolam less than that of diazepam (hint: volume of distribution or clearance)?

Midazolam and diazepam have similar volumes of distribution but midazolam (Versed) has a high clearance and diazepam (Valium) has a low clearance comparatively. Midazolam (Versed) also has a significantly higher hepatic clearance when compared to diazepam (Valium).

These last two sentences are stating the same thing. Total body clearance = sum of all individual organ clearances (hepatic + renal + ...). Since these drugs are primarily cleared by the liver, the fact that midazolam has a higher hepatic clearance implies that it will also have a higher total body clearance.

Benzodiazepines:
*Mechanism of Action: Bind to the gamma sub-unit of the GABA-A receptor. Their binding causes a structural modification of the receptor that results in an increase in GABA-A receptor activity.
*Side effects: Confusion, Hallucinations, Difficulty swallowing or breathing

Barbiturates:
*Mechanism of Action: Bind to the GABA-A receptor at the alpha subunit. Like benzodiazepines, barbiturates potentiate the effect of GABA at this receptor. Glutamate is the principal excitatory neurotransmitter in the CNS.
*Side effects: depression, confusion, or unusual excitement.
(The following is an answer submitted last year that explains this a bit differently). GABA is a neurotransmitter that when bound to its receptor allows for an influx of Cl- ions into the cell. This leads to hyperpolarization of the cell. Benzodiazepines bind to GABA receptors and enhance the effect of the GABA stimulation. Greater influx of Cl- makes it even more difficult for the cell to depolarize. SE include: drowsiness, confusion, ataxia (at high doses). Barbiturates also potentiate the effects of GABA stimulation, but the mechanism is different from benzodiazepines. Barbiturates increase the duration of the opening of the Cl- channel which also leads to difficulty in depolarization. Additionally, barbiturates can block excitatory glutamate receptors. This leads to decreased neuronal activity. SE include: drowsiness, impaired concentration, mental /physical sluggishness (synergistic with the effects of ethanol).

Buspirone:
*Mechanism of Action: Buspirone binds to 5-HT type 1A receptors thus inhibiting the firing rate of 5-HT-containing neurons. Buspirone also binds at dopamine type 2 (DA2) receptors, blocking presynaptic dopamine receptors.
*Side effects: headaches, dizziness, nervousness, light-headedness.
Buspirone is an antianxiety medication that is useful because it is not sedating and there is no cross-tolerance with other sedatives. It does not have muscle relaxant or anticonvulsant effects.

Hydroxyzine:
*Mechanism of Action: Hydroxyzine blocks histamine H1-receptors. Hydroxyzine competes with histamine for binding at H1-receptor sites on the effector cell surface, resulting in suppression of histaminic receptors
*Side effects: dizziness, hallucinations, decreased breathing, fatigue, drowsiness, nausea, vomiting, dry mouth and diarrhea
Hydroxyzine is a drug that is good for anxiety in patients with a history of substance abuse. It is also useful because it has anti-emetic properties.

Ethinol binds to acetylcholine, GABA, serontonin, and NMDA receptors. Metabolism is limited in the body, so ethanol leaves the body at a constant rate, rather than by following an elimination half-life. It is metabolized in the liver and excreted mainly in the kidneys.

Ethanol is metabolized by zero-order kinetics and not first order kinetics. Other notable drugs that are metabolized by zero-order processes are aspirin and phenytoin.

Ethanol has anxiolytic and sedative effects, but has high toxic potential. It's effects are seen at a range of doses and volume of distribution is almost the same as that of total body water. When combined with other sedative/hypnotics, CNS depression can be severe.

Chronic ethanol consumption can lead to liver disease and nutritional deficiencies. Ingestion of too much can lead to cardiomyopathy ("holiday heart"). Withdrawl symptoms can be severe.

In general, body water composition is greater in men than women, greater in younger people than older people, and greater in lean patients than in obese patients. When administered according to weight, peak blood alcohol levels will be lower in those people with larger body water compartments. This is also true of other water soluble drugs like succinylcholine.

Zolpidem: GABAa receptor agonist; used for short-term treatment of insomnia; onset of action 15 minutes and has half-life of 2-3 hours

Zaleplon: GABAa receptor agonist; used in the short-term treatment of insomnia; rapid onset of action and very short half-life of 1 hour

Ramelteon: selective MT1 and MT2 agonist in the suprachiasmatic nucleus, produces a melanin effect of inducing sleep; indicated for long-term treatment of insomnia when the primary complaint is falling asleep. Note, MT receptors are melatonin receptors.

Chloral hydrate: trichlorinated derivative of acetaldehyde that is converted to the active metabolite trichloroethanol, which enhances the GABA receptor complex; it is used for short-term treatment of insomnia and for sedation before minor medical or dental procedures

Diazpeam and lorazepam

Other drugs that you will have available include midazolam, thiopental (a barbiturate) and inhalational agents like isoflurane. You could stop the symptoms of a seizure with a muscle relaxant but NDMRs will have no effect on seizure activity in the brain. Of all these drugs, isoflurane is the most powerful anti-seizure medication you have available. Other traditional antiseizure medications like phenytoin are also available in the OR.

Know that barbiturates are weak acids, are highly protein bound, inhibit GABAa receptors, they are highly lipid soluble, they are metabolized by Phase 1 microsomal oxidative enzymes in liver, they may induce hepatic microsomal enzymes, and that like benzodiazepines their effects wear off by redistribution, they reduce ICP, and they may cause hypotension (vasodilation greater effect than negative inotropism).

Which one of the following statements is correct?

A. Benzodiazepines directly open chloride channels.

B. Benzodiazepines show analgesic actions.

C. Clinical improvement of anxiety requires 2 to 4   

    weeks of treatment with benzodiazepines.

D. All benzodiazepines have some sedative effects.

E. Benzodiazepines, like other CNS depressants, readily

    produce general anesthesia.

D. Although all benzodiazepines can cause sedation, the drugs labeled "benzodiazepines" in Figure 9.1 are promoted for the treatment of sleep disorder. Benzodiazepines enhance the binding of GABA to its receptor, which increases the permeability of chloride. The benzodiazepines do not relieve pain but may reduce the anxiety associated with pain. Unlike the TCA's and the MAO's, the benzodiazepines do not produce general anesthesia and, therefore, are relatively safe drugs with a high therapeutic index.

Which one of the following is a short-acting hypnotic?

A. Phenobarbital

B. Diazepam

C. Chlordiazepoxide

D. Triazolam

E. Flurazepam

D. Triazolam is an ultrashort-acting drug used as an 

    adjuvant to dental anesthesia.

Which one of the following statements is correct?

A. Phenobarbital shows analgesic properties

B. Diazepam and phenobarbital induce the P450 enzyme

    system.

C. Phenobarbital is useful in the treatment of acute 

    intermittent porphyria.

D. Phenobarbital induces respiratory depression, which

    is enhanced by the consumption of ethanol.

E. Buspirone has actions similar to those of the

    benzodiazepines.

D. Barbituates and ethanol are a potentially lethal combination. Phenobarbital is unable to alter the pain threshold. Only phenobarbital strongly induces the synthesis of the hepatic cytochrome P450 drug-metabolizing system. Phenobarbital is contraindicated in the treatment of acute intermittent porphyria. Buspirone lacks the anticonvulsant and muscle-relaxant properties of the benzodiazepines and causes only minimal sedation.

A 45yo man who has been injured in a car accident is brought into the emergency room. His blood alcohol level on admission is 275 mg/dl. Hospital records show a prior hospitalization for alcohol-related seizures. His wife confirms tha the has been drinking heavily for 3 weeks. What treatment should be provided to the patient if he goes into withdrawal?

A. None

B. Lorazepam

C. Pentobarbital

D. Phenytoin

E. Buspirone

B. It is important to treat the seizures associated with alcohol withdrawal. Benzodiazepines, such as chlordiazepoxide, diazepam, or the shorter-acting lorazepam, are effective in controlling this problem. They are less sedating than pentobarbital or phenytoin.