Drugs acting on CNS

Drugs acting on the CNS Anxiolytic and hypnotic drugs lecture 2  Dr. Ghada Taqa

Benzodiazepines Adverse Eeffects
Drowsiness; Confusion. Ataxia (high doses). Impaired Motor Performance. Cognitive impairment. Note: Triazolam, tolerance is frequent, rebound insomnia, day time amnesia & confusion. 5- Interaction with alcohol. 6-Dependency :High dose And Prolong treatment

Benzodiazepine Antagonists: Flumazenil

High affinity for the benzodiazepine receptor Act as selective competitive antagonists on GABA receptor. It is the only benzodiazepine receptor antagonist available for clinical use at present. Should be used IV produce effects within 1-2min

intravenously, flumazenil acts rapidly but has a short half-life (0.7–1.3 hours) due to rapid hepatic clearance. Undergoes extensive first pass metabolism Blocks action of benzodiazepines, zolpidem, & zaleplon but not other sedative/hypnotics.UsesReversing the central nervous system depressant effects of benzodiazepine overdose Hasten recovery following use of these drugs in anesthetic and diagnostic procedure

2- Non benzodiazepines

Zolpidem
Non benzodiazepine . Act on BZ1 receptors. & facilitate GABA mediated neuronal inhibition. Its action is antagonized by flumazenil. No anticonvulsant, or muscle relaxant effects. Rapid onset, short duration(3 hours). Uses a hypnotic drug for short term treatment of insomnia. Zaleplon Binds to BZs receptors and facilitate GABA actions. Short onset of action Rapid absorption

Other anxiolytic agent 

Buspirone mode of action: Serotonin agonist, activates 5-HT1A1 receptor Minimal sedation, less drowsiness, fatigue than most benzodiazepines Buspirone Used in the treatment of general anxiety disorder.


Barbiturate are second choice as sedative - hypnotic Mechanism of Action are less selective in action than BZD. Facilitation of GABA action on the brain. increase the duration of the GABA gated channel opening but in large dose, they can directly activating chloride channels. (not through BZD receptors). depress excitatory neurotransmitters action. Interfere with Na & K transport across cell membranes (reticular activating system inhibition).

Classification of barbiturates: Long acting( 24-28 h): Phenobarbitone Intermediate (8-24h): Amylobarbitone Short-acting(3-8h): Secobarbitone Amobarbital Ultrashort acting (25 minutes): thiopental


Pharmacokinetics All barbiturates are weak acids Are absorbed orally. Distribute throughout the body depending on lipid solubility e.g. thiobarbiturates are very lipid soluble with high rate of entry into CNS. Redistribute in the body from the brain to skeletal muscles - adipose tissues.

Pharmacological actions 1. CNS depression : a dose-dependent fashion.Sedative & hypnotic anesthesia in large doseAnticonvulsant action Coma and death.2. Respiratory depression: is dose –related. suppress hypoxic and chemoreceptor response to CO2 Large doses respiratory depression & death.

3. CVS depressions Healthy patient: at low doses, they have non significant effects. But in Hypovolemic states, CHF, normal doses may cause cardiovascular collapse. Large dose  circulatory collapse due to medullary vasomotor depression  direct vasodilatation.4. Enzyme induction. CYT P-450 microsomal enzymes inducers (Tolerance - drug interaction).

Therapeutic uses 

Anesthesia: The ultra-short-acting barbiturates, such as thiopental that used intravenously to induce anesthesia. Anticonvulsant: Phenobarbital is used in long-term management of tonic-clonic seizures. status epilepticus eclampsia.

3. drug of choice for treatment of young children with recurrent febrile seizures However, phenobarbital can depress cognitive performance in children, and the drug should be used cautiously. 4. Anxiety: Barbiturates have been used as mild sedatives to relieve anxiety, nervous tension, and insomnia. Most have been replaced by the benzodiazepines.

Adverse effects 

CNS: Barbiturates cause drowsiness, impaired concentration, and mental and physical sluggishness. Drug hangover: Hypnotic doses of barbiturates produce a feeling of tiredness well after the patient awakes. This drug hangover leads to impaired ability to function normally for many hours after waking. Occasionally, nausea and dizziness occur.

Precautions

barbiturates induce the P-450 system and therefore may decrease the effect of drugs that are metabolized by these hepatic enzymes.


Addiction
Abrupt withdrawal from barbiturates may cause: tremors. 2. Anxiety. 3. weakness. 4. Restlessness. 5. nausea and vomiting. 6. seizures. 7. delirium. cardiac arrest. Withdrawal is much more severe than that associated with opiates and can result in death.

Poisoning

Barbiturate poisoning has been a leading cause of death among drug overdoses for many decades . Severe depression of respiration is coupled with central cardiovascular depression, and results in a shock-like condition with shallow, infrequent breathing.

Treatment: includes artificial respiration and purging the stomach of its contents if the drug has been recently taken. Hemodialysis may be necessary if large quantities have been taken. Alkalinization of the urine often aids in the elimination of drug.

Drug interactions 1. Other CNS depressants: Ethanol 2. MAOI: potentiate CNS depression 3. Phenytoin, warfarin, and dicumarol: their metabolism is increased.

Advantages of BZD over barbiturate Selective: minimal respiratory and cardiovascular depression. 2. High therapeutic index. 3. Less hangover. 4. Not enzyme inducer. 5. Less dependence with minimal withdrawal symptoms. 6. Has specific antagonist.

Chloral hydrate

was developed in the late 1800s and is still used as a sedative–hypnotic agent. It has a disagreeable smell and taste.The drug is an effective sedative and hypnotic that induces sleep in about 30 minutes and lasts about 6 hours.It produces a high incidence of gastric irritation and allergic responses. occasionally causes cardiac arrhythmias.unreliable in patients with liver damage.

Antihistamines

Several H1 histamine antagonists : (e.g.diphenhydramine, promethazine, and hydroxyzine) Effective in treating mild types of insomnia. undesirable side effects that make them less useful than the benzodiazepines.

Antidepressants

Many antidepressants are effective in the treatment of chronic anxiety disorders and should be considered as first-line agents, especially in patients with concerns for addiction or dependence. Selective serotonin reuptake inhibitors (SSRIs)or serotonin/norepinephrine reuptake inhibitors (SNRIs), may be used alone or prescribed in combination with a low dose of a benzodiazepine during the first weeks of treatment.


Ethanol (ethyl alcohol)
It's a CNS depressant. Producing sedation and hypnosis with increasing dosage. Has antianxiety and sedative effects. It's toxic potential . Alcohol synergizes with many other sedative agents and can produce severe CNS depression with antihistamines or barbiturates.

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