A patient with a brain tumor has a grand mal seizure as he is entering the operating room. What drugs could you use to treat this seizure?

Diazpeam and lorazepam

1. Other drugs that you will have available include midazolam, thiopental (a barbiturate) and inhalational agents like isoflurane.

2. You could stop the symptoms of a seizure with a muscle relaxant but NDMRs will have no effect on seizure activity in the brain.

3. Of all these drugs, isoflurane is the most powerful anti-seizure medication you have available.

4. Other traditional antiseizure medications like phenytoin are also available in the OR.

BARBITURATES

Know that barbiturates are:

1. weak acids

2. highly protein bound

3. inhibit GABAa receptors

4. they are highly lipid soluble

5. they are metabolized by Phase 1 microsomal oxidative enzymes in liver

6. they may induce hepatic microsomal enzymes

7. like benzodiazepines their effects wear off by redistribution

8. they reduce ICP

9. they may cause hypotension (vasodilation greater effect than negative inotropism).

Very briefly discuss the mechanism of action and indications for zolpidem, zaleplon, ramelteon and chloral hydrate

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.
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

Briefly summarize the pharmacology of ethanol

1. Binds to Ach, GABA, 5HT, and NMDA receptors.

2. Metabolism is limited so ethanol leaves the body at a constant rate, rather than follow elimination half-life.

3. It is metabolized in the liver and excreted in the kidneys.
4. Ethanol is metabolized by zero-order kinetics

5. Other notable drugs that are metabolized by zero-order processes are aspirin and phenytoin.
6. Ethanol, anxiolytic/sedative effects/high toxic potential.

7. It's effects are seen at a range of doses and volume of distribution, almost the same as total body water.

8. When combined with other sedative/hypnotics, CNS depression can be severe.
9. 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.
10. H2O comp: men > women, young > older, learn > obese

11. When administered by weight, peak blood ETOH levels lower in those with larger H2O compartments.

12. This is also true of other water soluble drugs like succinylcholine.

Which class of drug is more clinically useful:

1. GABA agonists or antagonists?

2. NMDA agonists or antagonists?

Why?

Which class of drug is more clinically useful:

1. GABA agonists or antagonists?

2. NMDA agonists or antagonists?

Why?

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.

What are the:

1. Mechanism of action of benzodiazepines?

2. Therapeutic uses of benzodiazepines?

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.

What are the:

1. Mechanism of action of benzodiazepines?

2. Therapeutic uses of benzodiazepines?

Therapeutic uses include:

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

2. 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.

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

4. 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.

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

Briefly outline the pharmacology of flumazenil

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.

How does flumazenil compare to physostigmine?

Physostigmine (Antilirium)

1. Indirect acting cholinergic agonist.

2. Inhibits acetylcholinesterase.

3. Tertiary amine so it can cross the blood brain barrier with ease.

4. Physostigmine may be used to antagonize the delirium and CNS depressant effects of benzodiazepines

5. It could be useful to manage undesired effect of benzodiazepines.

6. 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.

7. 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.

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.

GHB is an agonist at the GHB receptor, which is excitatory

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.

Total body clearance = sum of all individual organ clearances 

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.

Compare the mechanisms of action and side-effects of:

1. benzodiazepines

2. barbiturates

3. buspirone

4. hydroxyzine

Benzodiazepines:
*Mechanism of Action: Bind To 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 drowsiness, confusion, ataxia (at high doses).

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.

Compare the mechanisms of action and side-effects of:

1. benzodiazepines

2. barbiturates

3. buspirone

4. hydroxyzin

Barbiturates:

Mechanism of Action:

1. Bind to the GABA-A receptors.

2.  Potentiate the effects of GABA stimulation, but the mechanism is different from benzodiazepines.

3. 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.

4. Glutamate is the principal excitatory neurotransmitter in the CNS

Side effects: depression, confusion, or unusual excitement, drowsiness, impaired concentration, mental /physical sluggishness (synergistic with the effects of ethanol).

Compare the mechanisms of action and side-effects of:

1. benzodiazepines

2. barbiturates

3. buspirone

4. hydroxyzin

Buspirone:

Mechanism of Action:

1. Buspirone binds to 5-HT type 1A receptors thus inhibiting the firing rate of 5-HT-containing neurons.

2. Buspirone also binds at dopamine type 2 (DA2) receptors, blocking presynaptic dopamine receptors

3. Buspirone is an antianxiety medication that is useful because it is not sedating and there is no cross-tolerance with other sedatives.

4. It does not have muscle relaxant or anticonvulsant effects.

Side effects: headaches, dizziness, nervousness, light-headedness

Compare the mechanisms of action and side-effects of:

1. benzodiazepines

2. barbiturates

3. buspirone

4. hydroxyzin

Hydroxyzine:

Mechanism of Action:

1. Hydroxyzine blocks histamine H1-receptors.

2. Competes with histamine for binding at H1-receptor sites on the effector cell surface, resulting in suppression of histaminic receptors

3. Good for anxiety in patients with a history of substance abuse.

4. Useful because it has anti-emetic properties.

Side effects: dizziness, hallucinations, decreased breathing, fatigue, drowsiness, nausea, vomiting, dry mouth and diarrhea

WHICH OF THE FOLLOWING STATEMENTS IS CORRECT?

A: BENZODIAZEPINES DIRECTLY OPEN CHLORIDE CHANNELS

B: BENZODIAZEPINES SHOW ANALGESIC ACTIONS

C: CLINICAL IMPROVEMENT OF ANXIETY REQUIRES 2-4 WEEKS OF TREATMENT WITH BENZODIAZEPINES

D: ALL BENZODIAZEPINES HAVE SOME SEDATIVE EFFECTS

E: BENZODIAZEPINES, LIKE OTHER CNS DEPRESSANTS, READILY PRODUCE GENERAL ANESTHESIA

Answer: D

BENZODIAZEPINES ENHANCE THE BINDING OF GABA TO ITS RECEPTOR, WHICH INCREASES THE PERMEABILITY OF CHLORIDE. THE BENZOS DO NOT RELIEVE PAIN BUT MAY REDUCE THE ANXIETY ASSOCIATED WITH PAIN. UNLIKE THE TCAS AND THE MAOS, THE BENZOS ARE EFFECTIVE WITHIN HOURS OF ADMINISTRATION. BENZOS DO NOT PRODUCE GENERAL ANESTHESIA AND ARE RELATIVELY SAFE DRUGS WITH A HIGH THERAPEUTIC INDEX.

WHICH ONE OF THE FOLLOWING IS A SHORT-ACTING HYPNOTIC?

A: PHENOBARBITAL

B: DIAZEPAM

C: CHLODIAZEPOXIDE

D: TRIAZOLAM

E: FLURAZEPAM

Answer: 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 INTERMITTENT PORPHYRIA

D: PHENOBARBITAL INDUCES RESPIRATORY DEPRESSION, WHICH IS ENHANCED BY THE CONSUMPTION OF ETHANOL

E: BUSPIRONE HAS ACTIONS SIMILAR TO THOSE OF THE BENZOS

Answer: D

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 ANTI-CONVULSANT AND MUSCLE-RELAXANT PROPERTIES OF THE BENZOS AND CAUSES ONLY MINIMAL SEDATION.

A 45 YEAR OLD MAN WHO HAS BEEN INJURED IN A CAR ACCIDENT IS BROUGHT INTO THE ER. HIS BLOOD ALCOHOL LEVEL ON ADMIT IS 275 MG/DL. HOSPITAL RECORDS SHOW A PRIOR HOSPITALIZATION FOR ALCOHOL RELATED SEIZURES. HIS WIFE CONFIRMS THAT HE HAS BEEN DRINKING HEAVILY FOR 3 WEEKS. WHAT TREATMENT SHOULD BE PROVIDED TO THE PATIENT IF HE GOES INTO WITHDRAWL?

A: NONE

B: LORAZEPAM

C: PENTOBARBITAL

D: PHENYTOIN

E: BUSPIRONE

Answer: B

TREAT THE SEIZURES ASSOCIATED WITH ALCOHOL WITHDRAWL. BENZOS (CHLODIAZEPOXIDE, DIAZEPAM, OR THE SHORTER ACTING THAN LORAZEPAM) ARE EFFECTIVE. THEY ARE LESS SEDATING THAN PENTOBARB OR PHENYTOIN.